PHARMACOLOGYPHARMACOLOGY(405)(405)

Dr Asra Hameed Dr Asra Hameed PharmD (JUW) PharmD (JUW)

asra_hameed1hotmailcomasra_hameed1hotmailcom

TOPICSBIOAVAILABILITYBIOEQUIVALENCETHERAPEUTIC INDEX

HISTORY HISTORY Phenytoin toxicity in epileptic Phenytoin toxicity in epileptic

patients which occurred in the year patients which occurred in the year 1968 in Australia1968 in Australia

The differences in the The differences in the bioavailabil i ty observed with bioavailabil i ty observed with different digoxin formulations in the different digoxin formulations in the year 1971year 1971

BioavailabilityBioavailability The extent and rate at which its active The extent and rate at which its active

moiety is delivered from pharmaceutical moiety is delivered from pharmaceutical form and becomes available in the form and becomes available in the systemic circulationsystemic circulation

Pharmacokineticsconc vs time

Co

nc

(mg

L)

Time (h)0 25

00

The ldquotrue doserdquo is not the drug swallowedBUT is the drug available to exert its effectbull1048708 Dissolutionbull1048708 Absorptionbull1048708 Survive metabolismMay have a drug with very low bioavailabilitybull1048708 Dosage form or drug may not dissolve readilybull1048708 Drug may not be readily pass across biological membranes (ie be absorbed)bull1048708 Drug may be extensively metabolized during absorption process (first-pass gut wall liver)Important component of overall variabilitybull1048708 Variable bioavailability may produce variable exposure

Why do we care about BIOAVAILABILITYWhy do we care about BIOAVAILABILITY

Route Bioavailabil i ty ()Route Bioavailabil i ty () Characteristics Intravenous 100 (by definit ion) Characteristics Intravenous 100 (by definit ion)

Most rapid onset (IV)Most rapid onset (IV) Intramuscular 75 to = 100 Large volumes Intramuscular 75 to = 100 Large volumes

often feasible may be (IM) painful often feasible may be (IM) painful Subcutaneous 75 to = 100 Smaller volumes Subcutaneous 75 to = 100 Smaller volumes

than IM may be painful (SC)than IM may be painful (SC) Oral (PO) 5 to lt 100 Most convenient f irst Oral (PO) 5 to lt 100 Most convenient f irst

pass effects may be signif icant pass effects may be signif icant Rectal (PR) 30 to lt 100 Less first-pass Rectal (PR) 30 to lt 100 Less first-pass

effects than oraleffects than oral Inhalation 5 to lt 100 Often very rapid onset Inhalation 5 to lt 100 Often very rapid onset Transdermal 80 to = 100 Usually very slow Transdermal 80 to = 100 Usually very slow

absorption used for lack of f irst-pass effects absorption used for lack of f irst-pass effects prolonged duration of actionprolonged duration of action

Objectives of bioavailabil i ty studies

Development of new formulation Determination of influence of excipients patient related factors and possible interaction with other drugs on the eff iciency of absorption

Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors storage stabil i ty on drug absorption

Primary stages of the development of a suitable dosage form for a new drug entity

Signif icance of Signif icance of Bioavailabil i ty Bioavailabil i ty Drugs having low therapeutic index eg cardiac

glycosides quinidine phenytoin etc Drugs whose peak levels are required for the effect

of drugs eg phenytoin phenobarbitone primidone sodium valporate anti-hypertensivesantidiabetics and antibiotics

Drugs that are absorbed by an active transporteg amino acid analogues Purine analogues etc

Drugs which are disintegrated in the alimentary canal and l iveregchiorpromazine etc or those which under go f irst pass metabolism

Formulations that give sustained release of drug formulations with smaller disintegration t ime than dissolut ion rate and drugs used as replacement therapy also warrant bioavailabil i ty test ing

In addit ion any new formulation has to be tested for its bioavailabil i ty profi le

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

TOPICSBIOAVAILABILITYBIOEQUIVALENCETHERAPEUTIC INDEX

HISTORY HISTORY Phenytoin toxicity in epileptic Phenytoin toxicity in epileptic

patients which occurred in the year patients which occurred in the year 1968 in Australia1968 in Australia

The differences in the The differences in the bioavailabil i ty observed with bioavailabil i ty observed with different digoxin formulations in the different digoxin formulations in the year 1971year 1971

BioavailabilityBioavailability The extent and rate at which its active The extent and rate at which its active

moiety is delivered from pharmaceutical moiety is delivered from pharmaceutical form and becomes available in the form and becomes available in the systemic circulationsystemic circulation

Pharmacokineticsconc vs time

Co

nc

(mg

L)

Time (h)0 25

00

The ldquotrue doserdquo is not the drug swallowedBUT is the drug available to exert its effectbull1048708 Dissolutionbull1048708 Absorptionbull1048708 Survive metabolismMay have a drug with very low bioavailabilitybull1048708 Dosage form or drug may not dissolve readilybull1048708 Drug may not be readily pass across biological membranes (ie be absorbed)bull1048708 Drug may be extensively metabolized during absorption process (first-pass gut wall liver)Important component of overall variabilitybull1048708 Variable bioavailability may produce variable exposure

Why do we care about BIOAVAILABILITYWhy do we care about BIOAVAILABILITY

Route Bioavailabil i ty ()Route Bioavailabil i ty () Characteristics Intravenous 100 (by definit ion) Characteristics Intravenous 100 (by definit ion)

Most rapid onset (IV)Most rapid onset (IV) Intramuscular 75 to = 100 Large volumes Intramuscular 75 to = 100 Large volumes

often feasible may be (IM) painful often feasible may be (IM) painful Subcutaneous 75 to = 100 Smaller volumes Subcutaneous 75 to = 100 Smaller volumes

than IM may be painful (SC)than IM may be painful (SC) Oral (PO) 5 to lt 100 Most convenient f irst Oral (PO) 5 to lt 100 Most convenient f irst

pass effects may be signif icant pass effects may be signif icant Rectal (PR) 30 to lt 100 Less first-pass Rectal (PR) 30 to lt 100 Less first-pass

effects than oraleffects than oral Inhalation 5 to lt 100 Often very rapid onset Inhalation 5 to lt 100 Often very rapid onset Transdermal 80 to = 100 Usually very slow Transdermal 80 to = 100 Usually very slow

absorption used for lack of f irst-pass effects absorption used for lack of f irst-pass effects prolonged duration of actionprolonged duration of action

Objectives of bioavailabil i ty studies

Development of new formulation Determination of influence of excipients patient related factors and possible interaction with other drugs on the eff iciency of absorption

Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors storage stabil i ty on drug absorption

Primary stages of the development of a suitable dosage form for a new drug entity

Signif icance of Signif icance of Bioavailabil i ty Bioavailabil i ty Drugs having low therapeutic index eg cardiac

glycosides quinidine phenytoin etc Drugs whose peak levels are required for the effect

of drugs eg phenytoin phenobarbitone primidone sodium valporate anti-hypertensivesantidiabetics and antibiotics

Drugs that are absorbed by an active transporteg amino acid analogues Purine analogues etc

Drugs which are disintegrated in the alimentary canal and l iveregchiorpromazine etc or those which under go f irst pass metabolism

Formulations that give sustained release of drug formulations with smaller disintegration t ime than dissolut ion rate and drugs used as replacement therapy also warrant bioavailabil i ty test ing

In addit ion any new formulation has to be tested for its bioavailabil i ty profi le

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

HISTORY HISTORY Phenytoin toxicity in epileptic Phenytoin toxicity in epileptic

patients which occurred in the year patients which occurred in the year 1968 in Australia1968 in Australia

The differences in the The differences in the bioavailabil i ty observed with bioavailabil i ty observed with different digoxin formulations in the different digoxin formulations in the year 1971year 1971

BioavailabilityBioavailability The extent and rate at which its active The extent and rate at which its active

moiety is delivered from pharmaceutical moiety is delivered from pharmaceutical form and becomes available in the form and becomes available in the systemic circulationsystemic circulation

Pharmacokineticsconc vs time

Co

nc

(mg

L)

Time (h)0 25

00

The ldquotrue doserdquo is not the drug swallowedBUT is the drug available to exert its effectbull1048708 Dissolutionbull1048708 Absorptionbull1048708 Survive metabolismMay have a drug with very low bioavailabilitybull1048708 Dosage form or drug may not dissolve readilybull1048708 Drug may not be readily pass across biological membranes (ie be absorbed)bull1048708 Drug may be extensively metabolized during absorption process (first-pass gut wall liver)Important component of overall variabilitybull1048708 Variable bioavailability may produce variable exposure

Why do we care about BIOAVAILABILITYWhy do we care about BIOAVAILABILITY

Route Bioavailabil i ty ()Route Bioavailabil i ty () Characteristics Intravenous 100 (by definit ion) Characteristics Intravenous 100 (by definit ion)

Most rapid onset (IV)Most rapid onset (IV) Intramuscular 75 to = 100 Large volumes Intramuscular 75 to = 100 Large volumes

often feasible may be (IM) painful often feasible may be (IM) painful Subcutaneous 75 to = 100 Smaller volumes Subcutaneous 75 to = 100 Smaller volumes

than IM may be painful (SC)than IM may be painful (SC) Oral (PO) 5 to lt 100 Most convenient f irst Oral (PO) 5 to lt 100 Most convenient f irst

pass effects may be signif icant pass effects may be signif icant Rectal (PR) 30 to lt 100 Less first-pass Rectal (PR) 30 to lt 100 Less first-pass

effects than oraleffects than oral Inhalation 5 to lt 100 Often very rapid onset Inhalation 5 to lt 100 Often very rapid onset Transdermal 80 to = 100 Usually very slow Transdermal 80 to = 100 Usually very slow

absorption used for lack of f irst-pass effects absorption used for lack of f irst-pass effects prolonged duration of actionprolonged duration of action

Objectives of bioavailabil i ty studies

Development of new formulation Determination of influence of excipients patient related factors and possible interaction with other drugs on the eff iciency of absorption

Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors storage stabil i ty on drug absorption

Primary stages of the development of a suitable dosage form for a new drug entity

Signif icance of Signif icance of Bioavailabil i ty Bioavailabil i ty Drugs having low therapeutic index eg cardiac

glycosides quinidine phenytoin etc Drugs whose peak levels are required for the effect

of drugs eg phenytoin phenobarbitone primidone sodium valporate anti-hypertensivesantidiabetics and antibiotics

Drugs that are absorbed by an active transporteg amino acid analogues Purine analogues etc

Drugs which are disintegrated in the alimentary canal and l iveregchiorpromazine etc or those which under go f irst pass metabolism

Formulations that give sustained release of drug formulations with smaller disintegration t ime than dissolut ion rate and drugs used as replacement therapy also warrant bioavailabil i ty test ing

In addit ion any new formulation has to be tested for its bioavailabil i ty profi le

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

BioavailabilityBioavailability The extent and rate at which its active The extent and rate at which its active

moiety is delivered from pharmaceutical moiety is delivered from pharmaceutical form and becomes available in the form and becomes available in the systemic circulationsystemic circulation

Pharmacokineticsconc vs time

Co

nc

(mg

L)

Time (h)0 25

00

The ldquotrue doserdquo is not the drug swallowedBUT is the drug available to exert its effectbull1048708 Dissolutionbull1048708 Absorptionbull1048708 Survive metabolismMay have a drug with very low bioavailabilitybull1048708 Dosage form or drug may not dissolve readilybull1048708 Drug may not be readily pass across biological membranes (ie be absorbed)bull1048708 Drug may be extensively metabolized during absorption process (first-pass gut wall liver)Important component of overall variabilitybull1048708 Variable bioavailability may produce variable exposure

Why do we care about BIOAVAILABILITYWhy do we care about BIOAVAILABILITY

Route Bioavailabil i ty ()Route Bioavailabil i ty () Characteristics Intravenous 100 (by definit ion) Characteristics Intravenous 100 (by definit ion)

Most rapid onset (IV)Most rapid onset (IV) Intramuscular 75 to = 100 Large volumes Intramuscular 75 to = 100 Large volumes

often feasible may be (IM) painful often feasible may be (IM) painful Subcutaneous 75 to = 100 Smaller volumes Subcutaneous 75 to = 100 Smaller volumes

than IM may be painful (SC)than IM may be painful (SC) Oral (PO) 5 to lt 100 Most convenient f irst Oral (PO) 5 to lt 100 Most convenient f irst

pass effects may be signif icant pass effects may be signif icant Rectal (PR) 30 to lt 100 Less first-pass Rectal (PR) 30 to lt 100 Less first-pass

effects than oraleffects than oral Inhalation 5 to lt 100 Often very rapid onset Inhalation 5 to lt 100 Often very rapid onset Transdermal 80 to = 100 Usually very slow Transdermal 80 to = 100 Usually very slow

absorption used for lack of f irst-pass effects absorption used for lack of f irst-pass effects prolonged duration of actionprolonged duration of action

Objectives of bioavailabil i ty studies

Development of new formulation Determination of influence of excipients patient related factors and possible interaction with other drugs on the eff iciency of absorption

Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors storage stabil i ty on drug absorption

Primary stages of the development of a suitable dosage form for a new drug entity

Signif icance of Signif icance of Bioavailabil i ty Bioavailabil i ty Drugs having low therapeutic index eg cardiac

glycosides quinidine phenytoin etc Drugs whose peak levels are required for the effect

of drugs eg phenytoin phenobarbitone primidone sodium valporate anti-hypertensivesantidiabetics and antibiotics

Drugs that are absorbed by an active transporteg amino acid analogues Purine analogues etc

Drugs which are disintegrated in the alimentary canal and l iveregchiorpromazine etc or those which under go f irst pass metabolism

Formulations that give sustained release of drug formulations with smaller disintegration t ime than dissolut ion rate and drugs used as replacement therapy also warrant bioavailabil i ty test ing

In addit ion any new formulation has to be tested for its bioavailabil i ty profi le

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

The ldquotrue doserdquo is not the drug swallowedBUT is the drug available to exert its effectbull1048708 Dissolutionbull1048708 Absorptionbull1048708 Survive metabolismMay have a drug with very low bioavailabilitybull1048708 Dosage form or drug may not dissolve readilybull1048708 Drug may not be readily pass across biological membranes (ie be absorbed)bull1048708 Drug may be extensively metabolized during absorption process (first-pass gut wall liver)Important component of overall variabilitybull1048708 Variable bioavailability may produce variable exposure

Why do we care about BIOAVAILABILITYWhy do we care about BIOAVAILABILITY

Route Bioavailabil i ty ()Route Bioavailabil i ty () Characteristics Intravenous 100 (by definit ion) Characteristics Intravenous 100 (by definit ion)

Most rapid onset (IV)Most rapid onset (IV) Intramuscular 75 to = 100 Large volumes Intramuscular 75 to = 100 Large volumes

often feasible may be (IM) painful often feasible may be (IM) painful Subcutaneous 75 to = 100 Smaller volumes Subcutaneous 75 to = 100 Smaller volumes

than IM may be painful (SC)than IM may be painful (SC) Oral (PO) 5 to lt 100 Most convenient f irst Oral (PO) 5 to lt 100 Most convenient f irst

pass effects may be signif icant pass effects may be signif icant Rectal (PR) 30 to lt 100 Less first-pass Rectal (PR) 30 to lt 100 Less first-pass

effects than oraleffects than oral Inhalation 5 to lt 100 Often very rapid onset Inhalation 5 to lt 100 Often very rapid onset Transdermal 80 to = 100 Usually very slow Transdermal 80 to = 100 Usually very slow

absorption used for lack of f irst-pass effects absorption used for lack of f irst-pass effects prolonged duration of actionprolonged duration of action

Objectives of bioavailabil i ty studies

Development of new formulation Determination of influence of excipients patient related factors and possible interaction with other drugs on the eff iciency of absorption

Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors storage stabil i ty on drug absorption

Primary stages of the development of a suitable dosage form for a new drug entity

Signif icance of Signif icance of Bioavailabil i ty Bioavailabil i ty Drugs having low therapeutic index eg cardiac

glycosides quinidine phenytoin etc Drugs whose peak levels are required for the effect

of drugs eg phenytoin phenobarbitone primidone sodium valporate anti-hypertensivesantidiabetics and antibiotics

Drugs that are absorbed by an active transporteg amino acid analogues Purine analogues etc

Drugs which are disintegrated in the alimentary canal and l iveregchiorpromazine etc or those which under go f irst pass metabolism

Formulations that give sustained release of drug formulations with smaller disintegration t ime than dissolut ion rate and drugs used as replacement therapy also warrant bioavailabil i ty test ing

In addit ion any new formulation has to be tested for its bioavailabil i ty profi le

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Route Bioavailabil i ty ()Route Bioavailabil i ty () Characteristics Intravenous 100 (by definit ion) Characteristics Intravenous 100 (by definit ion)

Most rapid onset (IV)Most rapid onset (IV) Intramuscular 75 to = 100 Large volumes Intramuscular 75 to = 100 Large volumes

often feasible may be (IM) painful often feasible may be (IM) painful Subcutaneous 75 to = 100 Smaller volumes Subcutaneous 75 to = 100 Smaller volumes

than IM may be painful (SC)than IM may be painful (SC) Oral (PO) 5 to lt 100 Most convenient f irst Oral (PO) 5 to lt 100 Most convenient f irst

pass effects may be signif icant pass effects may be signif icant Rectal (PR) 30 to lt 100 Less first-pass Rectal (PR) 30 to lt 100 Less first-pass

effects than oraleffects than oral Inhalation 5 to lt 100 Often very rapid onset Inhalation 5 to lt 100 Often very rapid onset Transdermal 80 to = 100 Usually very slow Transdermal 80 to = 100 Usually very slow

absorption used for lack of f irst-pass effects absorption used for lack of f irst-pass effects prolonged duration of actionprolonged duration of action

Objectives of bioavailabil i ty studies

Development of new formulation Determination of influence of excipients patient related factors and possible interaction with other drugs on the eff iciency of absorption

Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors storage stabil i ty on drug absorption

Primary stages of the development of a suitable dosage form for a new drug entity

Signif icance of Signif icance of Bioavailabil i ty Bioavailabil i ty Drugs having low therapeutic index eg cardiac

glycosides quinidine phenytoin etc Drugs whose peak levels are required for the effect

of drugs eg phenytoin phenobarbitone primidone sodium valporate anti-hypertensivesantidiabetics and antibiotics

Drugs that are absorbed by an active transporteg amino acid analogues Purine analogues etc

Drugs which are disintegrated in the alimentary canal and l iveregchiorpromazine etc or those which under go f irst pass metabolism

Formulations that give sustained release of drug formulations with smaller disintegration t ime than dissolut ion rate and drugs used as replacement therapy also warrant bioavailabil i ty test ing

In addit ion any new formulation has to be tested for its bioavailabil i ty profi le

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Objectives of bioavailabil i ty studies

Development of new formulation Determination of influence of excipients patient related factors and possible interaction with other drugs on the eff iciency of absorption

Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors storage stabil i ty on drug absorption

Primary stages of the development of a suitable dosage form for a new drug entity

Signif icance of Signif icance of Bioavailabil i ty Bioavailabil i ty Drugs having low therapeutic index eg cardiac

glycosides quinidine phenytoin etc Drugs whose peak levels are required for the effect

of drugs eg phenytoin phenobarbitone primidone sodium valporate anti-hypertensivesantidiabetics and antibiotics

Drugs that are absorbed by an active transporteg amino acid analogues Purine analogues etc

Drugs which are disintegrated in the alimentary canal and l iveregchiorpromazine etc or those which under go f irst pass metabolism

Formulations that give sustained release of drug formulations with smaller disintegration t ime than dissolut ion rate and drugs used as replacement therapy also warrant bioavailabil i ty test ing

In addit ion any new formulation has to be tested for its bioavailabil i ty profi le

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Signif icance of Signif icance of Bioavailabil i ty Bioavailabil i ty Drugs having low therapeutic index eg cardiac

glycosides quinidine phenytoin etc Drugs whose peak levels are required for the effect

of drugs eg phenytoin phenobarbitone primidone sodium valporate anti-hypertensivesantidiabetics and antibiotics

Drugs that are absorbed by an active transporteg amino acid analogues Purine analogues etc

Drugs which are disintegrated in the alimentary canal and l iveregchiorpromazine etc or those which under go f irst pass metabolism

Formulations that give sustained release of drug formulations with smaller disintegration t ime than dissolut ion rate and drugs used as replacement therapy also warrant bioavailabil i ty test ing

In addit ion any new formulation has to be tested for its bioavailabil i ty profi le

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

ABSOLUTE BIOAVAILABILITY

The systemic availabil i ty of a drug administered orally is determined in comparison to its iv administration

Characterization of a drugs absorption properties from the ev site

F = AUCev AUCiv

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

RELATIVE BIOAVAILABILITY

The availabil i ty of a drug product as compared to another dosage form or product of the same drug given in the same dose

Characterization of absorption of a drug from its formulation

Fr=AUCA AUCB

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

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Time (hours)

Co

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TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

DETERMINATION OF BIOAVAILABILITY

It is determined by It is determined by comparing plasma comparing plasma levels of a drug after levels of a drug after a particular route of a particular route of administration (eg administration (eg oral administration) oral administration) with plasma drug with plasma drug level achieved by IV level achieved by IV injection- in which all injection- in which all the agent rapidly the agent rapidly enters the enters the circulationcirculation

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

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50

60

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0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

When the drug is given orally only part When the drug is given orally only part of the administered dose appears in the of the administered dose appears in the plasma By plott ing plasma plasma By plott ing plasma concentrations of the drug versus time concentrations of the drug versus time one can measure the area under the one can measure the area under the curve (AUC) curve (AUC)

This curve reflects the extent of This curve reflects the extent of absorption of the drug absorption of the drug

[Note By definit ion this is 100 percent [Note By definit ion this is 100 percent for drugs delivered IV] for drugs delivered IV]

Bioavailabil i ty of a drug administered Bioavailabil i ty of a drug administered orally is the ratio of the area calculated orally is the ratio of the area calculated for oral administration compared with for oral administration compared with the area calculated for IV injection the area calculated for IV injection

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

The key parameters for determining The key parameters for determining bioavailabil i tybioavailabil i ty

1 AUC The AUC is proportional to the 1 AUC The AUC is proportional to the total amount of drug reaching the total amount of drug reaching the systemic circulation and thus systemic circulation and thus characterizes the extent of absorption characterizes the extent of absorption

2 Cmax Gives indication whether drug 2 Cmax Gives indication whether drug is sufficiently absorbed systemically to is sufficiently absorbed systemically to provide a therapeutic responseprovide a therapeutic response

3 Tmax The Tmax reflects the rate of 3 Tmax The Tmax reflects the rate of drug absorption and decreases as the drug absorption and decreases as the absorption rate increasesabsorption rate increases

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

B Factors that inf luence bioavailabi l i tyB Factors that inf luence bioavailabi l i ty First-pass hepatic metabolism When a drug is absorbed across the First-pass hepatic metabolism When a drug is absorbed across the

GI tract i t enters the portal circulat ion before entering the systemic GI tract i t enters the portal circulat ion before entering the systemic circulat ion (see Figure 13) I f the drug is rapidly metabolized by the circulat ion (see Figure 13) I f the drug is rapidly metabolized by the l iver the amount of unchanged drug that gains access to the l iver the amount of unchanged drug that gains access to the systemic circulat ion is decreased Many drugs such as propranolol systemic circulat ion is decreased Many drugs such as propranolol or l idocaine undergo signif icant biotransformation during a single or l idocaine undergo signif icant biotransformation during a single passage through the l iverpassage through the l iver

Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed Solubil i ty of the drug Very hydrophil ic drugs are poorly absorbed because of their inabil i ty to cross the l ipid-r ich cell membranes because of their inabil i ty to cross the l ipid-r ich cell membranes Paradoxical ly drugs that are extremely hydrophobic are also poorly Paradoxical ly drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body f luids absorbed because they are totally insoluble in aqueous body f luids and therefore cannot gain access to the surface of cells For a and therefore cannot gain access to the surface of cells For a drug to be readily absorbed it must be largely hydrophobic yet drug to be readily absorbed it must be largely hydrophobic yet have some solubil i ty in aqueous solut ions This is one reason why have some solubil i ty in aqueous solut ions This is one reason why many drugs are weak acids or weak bases There are some drugs many drugs are weak acids or weak bases There are some drugs that are highly l ipid-soluble and they are transported in the that are highly l ipid-soluble and they are transported in the aqueous solut ions of the body on carrier proteins such as albuminaqueous solut ions of the body on carrier proteins such as albumin

Chemical instabil i ty Some drugs such as penici l l in G are unstable Chemical instabil i ty Some drugs such as penici l l in G are unstable in the pH of the gastric contents Others such as insulin are in the pH of the gastric contents Others such as insulin are destroyed in the GI tract by degradative enzymesdestroyed in the GI tract by degradative enzymes

Nature of the drug formulation Drug absorption may be altered by Nature of the drug formulation Drug absorption may be altered by factors unrelated to the chemistry of the drug For example part icle factors unrelated to the chemistry of the drug For example part icle size salt form crystal polymorphism enteric coatings and the size salt form crystal polymorphism enteric coatings and the presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can inf luence the ease of dissolut ion and therefore alter the rate of inf luence the ease of dissolut ion and therefore alter the rate of absorptionabsorption

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

FACTORS INFLUENCING BIOAVAILABILITY Three distinct factors are involved Three distinct factors are involved

to influencing bioavailabil i tyto influencing bioavailabil i ty Pharmaceutical factorsPharmaceutical factors Patient related factorsPatient related factors Route of administrationRoute of administration

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

1Pharmaceutical factors1Pharmaceutical factors

Physicochemical properties of the Physicochemical properties of the drugdrug

1 Particle size 1 Particle size 2 Crystall ine structure2 Crystall ine structure 3 Salt form3 Salt formFormulation and manufacturing

variables 1Disintegration and dissolution t ime 1Disintegration and dissolution t ime 2Pharmaceutical ingredients2Pharmaceutical ingredients 3Special coatings3Special coatings 4Nature and type of dosage form4Nature and type of dosage form

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

2 Patient related factors2 Patient related factorsPhysiologic factors 1Variations in pH of GI f luids 1Variations in pH of GI f luids 2Gastric emptying rate 2Gastric emptying rate 3 Intestinal moti l i ty 3 Intestinal moti l i ty 4 Presystemic and first-pass metabolism 4 Presystemic and first-pass metabolism 5 Age sex 5 Age sex 6 Disease states6 Disease states Interactions with other

substances 1 Food 1 Food 2 Fluid volume 2 Fluid volume 3 Other drugs 3 Other drugs

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

3 Route of administration3 Route of administration

1Parentral administration1Parentral administration 2Oral administration2Oral administration 3Rectal administration 3Rectal administration 4Topical administration4Topical administration

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

BioequivalenceBioequivalence Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they

show comparable bioavailability and show comparable bioavailability and similar times to achieve peak blood similar times to achieve peak blood concentrations concentrations

Two related drugs with a significant Two related drugs with a significant difference in bioavailability are said to be difference in bioavailability are said to be bioinequivalentbioinequivalent

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

BioequivalenceBioequivalence

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

Time (hours)

Co

ncen

trat

ion

(ng

mL

)

TestGeneric

ReferenceBrand

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Goals of BEUltimate Bioequivalence studies impact of

changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the eff icacy is based

Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product

Important for l inking the commercial drug product to cl inical tr ial material at t ime of NDA

Important for post-approval changes in the marketed drug formulation

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Pharmaceutical Pharmaceutical EquivalentsEquivalents

Drug products are considered Drug products are considered pharmaceutical equivalents if they pharmaceutical equivalents if they contain the same active ingredient(s) contain the same active ingredient(s) have the same dosage form and route of have the same dosage form and route of administration and are identical in administration and are identical in strength or concentration strength or concentration

Equivalent products contain the same Equivalent products contain the same amount of ingredient in the same dosage amount of ingredient in the same dosage form but may differ in characteristics form but may differ in characteristics such as shape release mechanisms and such as shape release mechanisms and packagingpackaging

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Pharmaceutical Pharmaceutical Alternatives Alternatives

Drug products are considered pharmaceutical Drug products are considered pharmaceutical alternatives if they contain the same alternatives if they contain the same therapeutic moiety are different salts esters therapeutic moiety are different salts esters or complexes of the same moiety are or complexes of the same moiety are different dosage forms or are different different dosage forms or are different strengthsstrengths

Other pharmaceutical alternatives Other pharmaceutical alternatives Different dosage forms and strengths within a Different dosage forms and strengths within a

single product l ine by a single manufacturer single product l ine by a single manufacturer Extended-release formulations when Extended-release formulations when

compared with immediate- or standard-compared with immediate- or standard-release formulationsrelease formulations

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

THERAPEUTIC EQUIVALENCE

Two similar drugs are therpeutically equivaient if they have comparative eff icacy and safety

Two drugs that are bioequivalent may not be therapeutically equivalent

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Therapeutic index The therapeutic index of a drug is the ratio

of the dose that produces toxicity to the dose that produces a cl inically desired or effective response in a population of individuals

where TD50 = the drug dose that produces a toxic effect in half the population and ED50 = the drug dose that produces a therapeutic or desired response in half the population

The therapeutic index is a measure of a drugs safety because a larger value indicates a wide margin between doses that are effective and doses that are toxic

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Narrow therapeutic indexNarrow therapeutic index having little difference between toxic and having little difference between toxic and

therapeutic doses therapeutic doses

Large therapeutic indexLarge therapeutic index A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low

one this corresponds to a situation in which one this corresponds to a situation in which one would have to take a much higher amount one would have to take a much higher amount of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to do good do good

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Determination of therapeutic indexDetermination of therapeutic index The therapeutic index is determined by measuring The therapeutic index is determined by measuring

the frequency of desired response and toxic the frequency of desired response and toxic response at various doses of drug By convention response at various doses of drug By convention the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and the toxic effect in fi f ty percent of the population are the toxic effect in fi f ty percent of the population are employed these are known as the ED50 and TD50 employed these are known as the ED50 and TD50 respectivelyrespectively

In humans the therapeutic index of a drug is In humans the therapeutic index of a drug is determined using drug trials and accumulated determined using drug trials and accumulated clinical experience These usually reveal a range of cl inical experience These usually reveal a range of effective doses and a different (sometimes effective doses and a different (sometimes overlapping) range of toxic dosesoverlapping) range of toxic doses

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Although some drugs have narrow Although some drugs have narrow therapeutic indices they are routinely therapeutic indices they are routinely used to treat certain diseasesused to treat certain diseases

Several lethal diseases such as Several lethal diseases such as Hodgkins lymphoma are treated with Hodgkins lymphoma are treated with narrow therapeutic index drugs however narrow therapeutic index drugs however treatment of a simple headache for treatment of a simple headache for example with a narrow therapeutic index example with a narrow therapeutic index drug would be unacceptable drug would be unacceptable

Figure shows the responses to warfarin Figure shows the responses to warfarin an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow therapeutic index and penicil l in an therapeutic index and penicil l in an antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic indexindex

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

WarfarinWarfarin Warfarin (example of a drug with a

small therapeutic index) As the dose of warfarin is increased a As the dose of warfarin is increased a

greater fraction of the patients respond greater fraction of the patients respond (for this drug the desired response is a (for this drug the desired response is a two-fold increase in prothrombin time) two-fold increase in prothrombin time) unti l eventually all patients respondunti l eventually all patients respond

However at higher doses of warfarin a However at higher doses of warfarin a toxic response occurs namely a high toxic response occurs namely a high degree of anticoagulation that results in degree of anticoagulation that results in hemorrhagehemorrhage

When the therapeutic index is low it is When the therapeutic index is low it is possible to have a range of possible to have a range of concentrations where the effective and concentrations where the effective and toxic responses overlap toxic responses overlap

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

That is some patients hemorrhage That is some patients hemorrhage whereas others achieve the desired whereas others achieve the desired two-fold prolongation of prothrombin two-fold prolongation of prothrombin time t ime

Variation in patient response is Variation in patient response is therefore most l ikely to occur with a therefore most l ikely to occur with a drug showing a narrow therapeutic drug showing a narrow therapeutic index because the effective and toxic index because the effective and toxic concentrations are similarconcentrations are similar

Agents with a low therapeutic indexmdashAgents with a low therapeutic indexmdashthat is drugs for which dose is crit ically that is drugs for which dose is crit ically importantmdashare those drugs for which importantmdashare those drugs for which bioavailabil i ty crit ically alters the bioavailabil i ty crit ically alters the therapeutic effectstherapeutic effects

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Penici l l inPenici l l in Penicil l in (example of a drug with a

large therapeutic index) For drugs such as penicil l in it is For drugs such as penicil l in it is

safe and common to give doses in safe and common to give doses in excess (often about ten-fold excess (often about ten-fold excess) of that which is minimally excess) of that which is minimally required to achieve a desired required to achieve a desired response response

In this case bioavailabil i ty does not In this case bioavailabil i ty does not crit ically alter the therapeutic crit ically alter the therapeutic effectseffects

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

MARIYAM ATHERMARIYAM ATHER

CONCLUSION

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

BIOAVAILABILIT Bioavailabil i ty is the fraction of Bioavailabil i ty is the fraction of

administered drug that reaches the administered drug that reaches the systemic circulationsystemic circulation

Bioavailabil i ty is expressed as the Bioavailabil i ty is expressed as the fraction of administered drug that gains fraction of administered drug that gains access to the systemic circulation in a access to the systemic circulation in a chemically unchanged formchemically unchanged form

For example if 100 mg of a drug are For example if 100 mg of a drug are administered orally and 70 mg of this administered orally and 70 mg of this drug are absorbed unchanged the drug are absorbed unchanged the bioavailabil i ty is 07 or seventy percent bioavailabil i ty is 07 or seventy percent

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

BIOEQUIVALENCE Two related drugs are bioequivalent Two related drugs are bioequivalent

if they show comparable if they show comparable bioavailabil i ty and similar t imes to bioavailabil i ty and similar t imes to achieve peak blood concentrations achieve peak blood concentrations

Two related drugs with a signif icant Two related drugs with a signif icant difference in bioavailabil i ty are said difference in bioavailabil i ty are said to be bioinequivalentto be bioinequivalent

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals