pharmacokinetics §pk process in the body §kinetic processes 张翔南 浙江大学药学院...
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PharmacokineticsPharmacokineticsPK process in the bodyPK process in the body
Kinetic processesKinetic processes
张翔南浙江大学药学院
[email protected]医学院科研楼 B404
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
1 Overview1 Overview
2 2 Transport of Drug in the BodyTransport of Drug in the Body
3 Pharmacokinetic Processes of the Drug3 Pharmacokinetic Processes of the Drug
in the Bodyin the Body
1.1. OverviewOverview
ADMEADMEof the drug inof the drug in
human bodyhuman body
2.2. Transport of Drug in the Body Transport of Drug in the Body
2.1 Transmembrane Transport of 2.1 Transmembrane Transport of DrugsDrugs
(1) Passive Transport(1) Passive Transport Simple diffusionSimple diffusion (简单扩散)(简单扩散) FiltrationFiltration (滤过)(滤过)
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Characteristics of Passive TransportCharacteristics of Passive Transport
not involving specific carriers not involving specific carriers Energy-independentEnergy-independent no saturabilityno saturability no competition with other drugsno competition with other drugs Concentration gradient (down-hill)Concentration gradient (down-hill)
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
(2) Active Transport(2) Active Transport
Characteristics of active transportCharacteristics of active transport
Involving specific carrier Involving specific carrier Energy-dependentEnergy-dependent SaturabilitySaturability Competition at same carrierCompetition at same carrier Moving against concentration gradient (up-hill)Moving against concentration gradient (up-hill)
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
(3) Others(3) Others
Filtration through poresFiltration through pores ( 膜 孔 滤( 膜 孔 滤过)过)
Facilitated diffusionFacilitated diffusion (易化扩散)(易化扩散) EndocytosisEndocytosis (内吞)(内吞) PinocytosisPinocytosis (胞饮)(胞饮) Ion-pair transportIon-pair transport (离子对转运)(离子对转运)
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Three types of functional membrane proteins.Three types of functional membrane proteins.
Transporters Transporters of drugs in PK of drugs in PK processesprocesses
Simple diffusionSimple diffusion
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Determinants of simple diffusionDeterminants of simple diffusion
For most drugs of small molecules (usually For most drugs of small molecules (usually are weak acids or weak bases):are weak acids or weak bases):
Lipid-soluble or un-ionized formsLipid-soluble or un-ionized forms
pKa pKa of the drug andof the drug and pHpH of the body fluidof the body fluid
The The pKapKa is that pH at which the concentrations of is that pH at which the concentrations of the ionized and un-ionized forms are equal.the ionized and un-ionized forms are equal.
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Henderson-Hasselbalch equationHenderson-Hasselbalch equation
Weak acid drugs: Weak acid drugs: ppH - H - ppKa = log ( [AKa = log ( [A--] / [HA] )] / [HA] ) ppKa - Ka - ppH = log ( [HA] / [AH = log ( [HA] / [A--] )] )
Weak base drugs:Weak base drugs: ppKa - Ka - ppH = log ( [BHH = log ( [BH++] / [B] )] / [B] ) ppH - H - ppKa = log ( [B] / [BHKa = log ( [B] / [BH++] )] )
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
ppHH ppKaKaun-ionized un-ionized
formformlipid-lipid-solublesoluble
Simple Simple diffusiondiffusion
Weak Weak acidsacids
Weak Weak basesbases
And / orAnd / or
And / orAnd / or
And / orAnd / or
And / orAnd / or
pH < pKa:pH < pKa: HA and BHHA and BH+ + are predominantare predominant
pH > pKa:pH > pKa: AA - - and B are predominantand B are predominant
ImplicationsImplications
Absorption Absorption
DistributionDistribution
ExcretionExcretion
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
2.2 Free and Bound Forms2.2 Free and Bound Forms
Plasma protein bindingPlasma protein binding
Tissue / organ affinityTissue / organ affinity
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
3.3. Fate of the drug in the body Fate of the drug in the body
AbsorptionAbsorption DistributionDistribution BiotransformationBiotransformation ( metabolism)( metabolism) ExcretionExcretion - - ADMEADME
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
3.1 Absorption3.1 Absorption Absorption is the transfer of a drug from its site of Absorption is the transfer of a drug from its site of
administration to the blood stream.administration to the blood stream.
Gastrointestinal tractGastrointestinal tract Parenteral injection Parenteral injection im. sc.im. sc. InhalationInhalation Transdermal Transdermal
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
(1) Gastrointestinal tract(1) Gastrointestinal tract
Route:Route: OralOral SublingualSublingual RectalRectal
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Factors influencing absorption:Factors influencing absorption:
blood flow to the absorption siteblood flow to the absorption site total surface area available for absorptiontotal surface area available for absorption contact time at the absorption surfacecontact time at the absorption surface physic-chemical properties of the drugphysic-chemical properties of the drug first-pass eliminationfirst-pass elimination
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
First-pass elimination First-pass elimination
When a drug is absorbed across the GI tract, When a drug is absorbed across the GI tract, it enters the portal circulation before entering it enters the portal circulation before entering the systemic circulation. If the drug is rapidly the systemic circulation. If the drug is rapidly metabolized by the liver, the amount of metabolized by the liver, the amount of unchanged drug that gains access to the unchanged drug that gains access to the systemic circulation is decreased.systemic circulation is decreased.
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
First-pass First-pass eliminationelimination
(2) Parenteral injection(2) Parenteral injection
intramuscular injection ( im ) intramuscular injection ( im ) subcutaneous injection ( sc )subcutaneous injection ( sc )
DeterminantsDeterminants Local blood flowLocal blood flow Solubility of the drug Solubility of the drug
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
(3) Others(3) Others
InhalationInhalation IntranasalIntranasal Transdermal Transdermal Topical Topical
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
3.2 Distribution3.2 Distribution
Drug distribution is the process by which a Drug distribution is the process by which a drug reversibly leaves the blood stream and drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) enters the interstitium (extracellular fluid) and / or the cells of the tissues.and / or the cells of the tissues.
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Body fluid Body fluid volume:volume:
Sites of drug Sites of drug
distributiondistribution
(1) Binding of drug to plasma proteins(1) Binding of drug to plasma proteins
Bound drug: Bound drug: Inactive temporilyInactive temporily can not distributioncan not distribution reversible (storage form)reversible (storage form) percentage of bindingpercentage of binding competitively displacement competitively displacement
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
competitively displacementcompetitively displacement Class I drugs:Class I drugs: Dose less than available binding Dose less than available binding
sites. sites. Most drug molecules are bound to the Most drug molecules are bound to the proteins and free drug concentration is low.proteins and free drug concentration is low.
Class II drugs:Class II drugs: Dose greater than available Dose greater than available binding sites. binding sites. Most proteins contain a bound Most proteins contain a bound drug and free drug concentration is significant.drug and free drug concentration is significant.
Class I + Class II drugs:Class I + Class II drugs: Displacement of Displacement of Class I drug occures when a Class II drug is Class I drug occures when a Class II drug is administered simultaneously.administered simultaneously.
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
(2) Physic-chemical properties of the drug(2) Physic-chemical properties of the drug
(3) Blood flow and re-distribution(3) Blood flow and re-distribution
(4) Affinity to organs or tissues(4) Affinity to organs or tissues
(5) Barriers(5) Barriers
Blood-brain barrier (BBB)Blood-brain barrier (BBB)
Placental barrierPlacental barrier
Blood-eye barrier Blood-eye barrier
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Blood-brain barrier (BBB)Blood-brain barrier (BBB)
Able to pass throughAble to pass through Unable to pass throughUnable to pass through
Small moleculesSmall molecules Large moleculesLarge molecules
Lipid-solubleLipid-soluble Water-solubleWater-soluble
Transporter-mediation Transporter-mediation
Structure of liver Structure of liver capillary and brain capillary and brain
capillarycapillary
Amount of drug passing through blood-Amount of drug passing through blood-brain barrierbrain barrier
Percentage of drug in Percentage of drug in c.s.f.c.s.f.
Increases whenIncreases when
InflammationInflammation
Larger doses usedLarger doses used
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
BBB BBB permeability permeability increases in increases in
inflammationinflammation
Placental barrier:Placental barrier:
More permeableMore permeable
3.3 Biotransformation (drug metabolism)3.3 Biotransformation (drug metabolism)
(1) Biotransformation sites(1) Biotransformation sites
Liver:Liver: most of the drugsmost of the drugs Other organs/tissues:Other organs/tissues: intestine, kidney, intestine, kidney,
lung, plasma, etc.lung, plasma, etc.
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
(2) Phases of biotransformation(2) Phases of biotransformation
Phase I: Phase I: Oxidation reduction hydrolysisOxidation reduction hydrolysis most drugs are inactivatedmost drugs are inactivated few (few (prodrugsprodrugs) are activated) are activated
Phase II: Phase II: ConjugationConjugation inactivatedinactivated
Metabolites: Metabolites: more water-soluble more water-soluble easier to excreteeasier to excrete
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Drugs or other substancesDrugs or other substances Phase IPhase I
inactivatedinactivated (( few: activatefew: activatedd ))
Phase IIPhase II
inactivatedinactivated
ExcretionExcretion
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
(3) Enzymes in biotransformation(3) Enzymes in biotransformation
Enzymes in Phase I: Enzymes in Phase I: cytochrome-P450cytochrome-P450 many other enzymesmany other enzymes
Enzymes in Phase II: Enzymes in Phase II: acetylase acetylase glucuronosyltransferaseglucuronosyltransferase etc.etc.
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Superfamily of Superfamily of cytochrome-P450cytochrome-P450
CYP3A4CYP3A4(( cytochrome / cytochrome /
family / subfamily / family / subfamily / membermember ))
(4) Hepatic enzymes of drug metabolism(4) Hepatic enzymes of drug metabolism
hepatic microsomal mixed function oxidase hepatic microsomal mixed function oxidase system system (肝药酶)(肝药酶)
Extraction > 0.7: Extraction > 0.7: hepatic blood flow hepatic blood flow dependentdependent
- - nitroglucerin, propranolol, …nitroglucerin, propranolol, …Extraction < 0.3: Extraction < 0.3: hepatic enzyme dependenthepatic enzyme dependent - - diazepam, phenobarbital, …diazepam, phenobarbital, …
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Induction of hepatic enzymes by drugsInduction of hepatic enzymes by drugs example: example: phenobarbitalphenobarbital -- steroids, warfarinsteroids, warfarin
Inhibition of hepatic enzymes by drugsInhibition of hepatic enzymes by drugs example: example: cimetidinecimetidine -- diazepamdiazepam
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
肝药酶诱导剂对双香豆素血浓度及凝血作用的影响肝药酶诱导剂对双香豆素血浓度及凝血作用的影响
3.4 Excretion3.4 Excretion
(1) Excretion routes(1) Excretion routes KidneyKidney BileBile LungLung GI tractGI tract MilkMilk Secretion glandsSecretion glands
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
(2) Renal excretion(2) Renal excretion
Glomerular filtrattionGlomerular filtrattion renal blood flowrenal blood flow
Active tubule secretionActive tubule secretion specific carriers / competitionspecific carriers / competition
Passive tubule reabsorptionPassive tubule reabsorption urine pH, urine flowurine pH, urine flow
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Renal excretionRenal excretion
Glumerular fitrationGlumerular fitration
Active secretionActive secretion
Passive reabsorptionPassive reabsorption
(3) Bile excretion(3) Bile excretion
Carrier-mediated activeCarrier-mediated active
transporttransport
Hepato-enteral circulationHepato-enteral circulation
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
3.5 Elimination and Accumulation3.5 Elimination and Accumulation
Elimination:Elimination: BiotransformationBiotransformation ExccretionExccretion Distribution (stored in fat, hair, etc)Distribution (stored in fat, hair, etc)
Accumulation:Accumulation: Dosing rate > elimination rate Dosing rate > elimination rate
Part APart A Pharmacokinetic ProcessesPharmacokinetic Processes
Part BPart B Kinetic ProcessesKinetic Processes
1 Drug concentration-time curve1 Drug concentration-time curve
2 Kinetic rate processes2 Kinetic rate processes
3 Pharmacokinetic models3 Pharmacokinetic models
4 Pharmacokinetic parameters and 4 Pharmacokinetic parameters and implicationsimplications
5 Multiple dosing5 Multiple dosing
Part BPart B Kinetic ProcessesKinetic Processes
1.1. Drug concentration-time curve Drug concentration-time curve (C-T curve)(C-T curve)
Maximal (peak) concentration:Maximal (peak) concentration: CCmaxmax C Cpp
Time to maximal concentration (Peak time ) :Time to maximal concentration (Peak time ) : TTmaxmax T Tpp
Area under the curve:Area under the curve: AUCAUC Multiple dosing (steady state): Multiple dosing (steady state):
CCssss max max C Css minss min C Cssss
t
C
i.m.i.m.
s.c.s.c.
OralOral
i.v.i.v.
←
←
←
←
CCmaxmax
CCpp
↑ ↑ ↑TTmax, max, TTpp
TTmaxmax 、、 CCmaxmax and AUC and AUC
↑Tmax
←Cmax
AUC↙
C-T curve after multiple dosing C-T curve after multiple dosing (( same dose and intervalsame dose and interval ))
Temporal characteristics of drug effect and Temporal characteristics of drug effect and relattionship to therapeutic windowrelattionship to therapeutic window
2. 2. Kinetic rate processesKinetic rate processes
dC / dt dC / dt = = KCKCnn
Part BPart B Kinetic ProcessesKinetic Processes
2.1 Zero order kinetics2.1 Zero order kinetics
n n = = 00 dC / dt dC / dt = -= - KK CCt t = = CC00 -- K tK t CC00 -- Ct Ct = = K tK t when Cwhen Ctt == 1/2 C1/2 C00,,
then then t = tt = t1/21/2, 0.5 C, 0.5 C00 == K tK t1/2 1/2
tt1/21/2 == 0.5 C0.5 C0 0 / K/ K
Part BPart B Kinetic ProcessesKinetic Processes
Zero order kineticsZero order kinetics
A.A. same amounts of drug are same amounts of drug are eliminated per unit timeeliminated per unit time
B. B. t t1/21/2 is not a constant is not a constant
C. C. C-T curve is linear C-T curve is linear
D. D. no Css theoretically no Css theoretically
Part BPart B Kinetic ProcessesKinetic Processes
Kinetic properties of C-T curves after Kinetic properties of C-T curves after single bolus injection of drugsingle bolus injection of drug
2.2 First order kinetics2.2 First order kinetics n n = = 11 dC / dt dC / dt = -= - KCKC CCt t = = CC00ee -- KtKt lnClnCt t = = lnClnC00 -- Kt Kt KtKt == lnClnC00 -- lnClnCtt == ln(Cln(C00 / C / Ctt)) when Cwhen Ctt == 1/2C1/2C00 ,, tt == tt1/21/2 ,, tt1/21/2 == ln2/Kln2/K == 0.693/K0.693/K
Part BPart B Kinetic ProcessesKinetic Processes
First order kineticsFirst order kinetics
A.A. eliminated at same rate per unit time eliminated at same rate per unit time
B.B. t t1/21/2 is a constant is a constant
C.C. logC-T curve is linear logC-T curve is linear
D.D. steady state (Css) after 4-5 t steady state (Css) after 4-5 t1/21/2
Part BPart B Kinetic ProcessesKinetic Processes
Kinetic properties of C-T curves after Kinetic properties of C-T curves after single bolus injection of drugsingle bolus injection of drug
2.3 Non-linear kinetics2.3 Non-linear kinetics
Higher concentration (or dose):Higher concentration (or dose): zero order kineticszero order kineticsLowerconcentration (or dose):Lowerconcentration (or dose): first order kineticsfirst order kinetics
Because of limits in elimination capacity Because of limits in elimination capacity Examples:Examples: aspirin, phenytoin, ethanolaspirin, phenytoin, ethanol
Part BPart B Kinetic ProcessesKinetic Processes
Michaelis-Menten kineticsMichaelis-Menten kinetics
dC / dt = VdC / dt = Vmax max C / (KC / (Kmm + C) + C) if if Km >> C Km >> C dC / dt = VdC / dt = Vmax max C / KC / Kmm
VVmaxmax / K / Kmm = K = Ke e - - First orderFirst order
ifif C >> Km C >> Km dC / dt = VdC / dt = Vmax max C / CC / C dC / dt = -VdC / dt = -Vmaxmax - - Zero orderZero order
Part BPart B Kinetic ProcessesKinetic Processes
Kinetic properties of C-T curves after Kinetic properties of C-T curves after single bolus injection of drugsingle bolus injection of drug
3 3 Pharmacokinetic modelsPharmacokinetic models
2.1 One-compartment model2.1 One-compartment model
If the drug rapidly distributed in the body If the drug rapidly distributed in the body after administration, then eliminated at after administration, then eliminated at same rate.same rate.
Part BPart B Kinetic ProcessesKinetic Processes
One-compartment modelOne-compartment model
BodyBody logC
t
iv
Part BPart B Kinetic ProcessesKinetic Processes
D E
2.2 Two-compartment model2.2 Two-compartment model
D → → E D → → E
↑↓ ↑↓
PeripheralPeripheral
CentralCentral
First, enter the centralFirst, enter the central
compartmentcompartment
Then, distributed to Then, distributed to peripheral compartment, peripheral compartment, and eliminnatedand eliminnated
CentralCentral
PeripheralPeripheral
Part BPart B Kinetic ProcessesKinetic Processes
D → → E
↑↓logC
t
iv
α β
βα
Distribution over, Distribution over, and eliminationand elimination
C-T curveC-T curve
CentralCentral
PeripheralPeripheral
DistributionDistribution EliminationElimination
Part BPart B Kinetic ProcessesKinetic Processes
2.3 Other models2.3 Other models
Physiological pharmacokinetic modelPhysiological pharmacokinetic model
Combined pharmacokinetic-Combined pharmacokinetic- pharmacodynamic modelpharmacodynamic model
Statistical momentStatistical moment
Part BPart B Kinetic ProcessesKinetic Processes
4. 4. Pharmacokinetic parameters and Pharmacokinetic parameters and their implicationstheir implications
4.1 Bioavailability 4.1 Bioavailability ( F )( F )
Bioavailability is the fraction of Bioavailability is the fraction of administered drug (oral) that reaches the administered drug (oral) that reaches the systemic circulationsystemic circulation
Part BPart B Kinetic ProcessesKinetic Processes
Absolute bioavailabilityAbsolute bioavailability
F = AUCF = AUC(po, sc, im)(po, sc, im) / AUC / AUC (iv)(iv)
Relative bioavailabilityRelative bioavailability
F = AUCF = AUC(tested)(tested) / AUC / AUC(standard)(standard)
Implication:Implication: Evaluation for absorption Evaluation for absorption and drug quality controland drug quality control
Part BPart B Kinetic ProcessesKinetic Processes
4.2 Apparent volume of distribution (4.2 Apparent volume of distribution (VdVd))
The volume of distribution (Vd) relates the The volume of distribution (Vd) relates the amount of drug in the body to the concentration amount of drug in the body to the concentration of drug (C) in the blood or plasma.of drug (C) in the blood or plasma. iv iv Vd = D / C Vd = D / C popo Vd = FD / C Vd = FD / C
Part BPart B Kinetic ProcessesKinetic Processes
Implications of VImplications of Vdd
Ratio of drug amount and plasma drug Ratio of drug amount and plasma drug concentrationconcentration
Properties of drug distributionProperties of drug distribution
Used for pharmacokinetic calculationUsed for pharmacokinetic calculation
Part BPart B Kinetic ProcessesKinetic Processes
4.3 Half-life (4.3 Half-life (tt1/21/2))
The half-life (tThe half-life (t1/21/2) is the time takes for the ) is the time takes for the plasma concentration or the amount of drug in plasma concentration or the amount of drug in the body reduced by 50%.the body reduced by 50%.
tt1/21/2 = 0.693 / Ke = 0.693 / Ke = = Vd / ClVd / Cl
Part BPart B Kinetic ProcessesKinetic Processes
Implications of Implications of tt1/21/2
Elimination rateElimination rate
Estimating the times of fully elimination and Estimating the times of fully elimination and reaching steady statereaching steady state
Classifying short- and long-acting drugsClassifying short- and long-acting drugs
Adjusting dosage regimens for patients with Adjusting dosage regimens for patients with hepatic or renal failureshepatic or renal failures
Part BPart B Kinetic ProcessesKinetic Processes
Elimination of single dose and accumulation after multiple dosing (at same dose and interval) of a first order kinetic drug
Elimination after single dosingElimination after single dosing
t1/2 0 100%
1 50%
2 25%
3 12.5%
4 6.25%
5 3.13%
6 1.57%
…………
Accumulation after multiple Accumulation after multiple dosing at same dose and dosing at same dose and intervalinterval (( tt1/21/2))
t1/2 0 0 ~ 100%
1 50 ~ 150%
2 75 ~ 175%
3 87.5 ~ 187.5%
4 93.8 ~ 193.8%
5 96.9 ~ 196.9%
6 98.4 ~ 198.4%
…………
4.4 Clearance (Cl)4.4 Clearance (Cl)
A A constant fractionconstant fraction of drug in the body is eliminated of drug in the body is eliminated per unit of time (per unit of time (first-order kineticsfirst-order kinetics).).
Cl = Ke Cl = Ke Vd Vd A A constant amountconstant amount of drug in the body is eliminated of drug in the body is eliminated per unit of time (per unit of time (zero-order kineticszero-order kinetics).).
4.5 Elimination rate constant (Ke)4.5 Elimination rate constant (Ke)
KeKe = 0.693 / = 0.693 / tt1/21/2 = = Cl / VdCl / Vd
Part BPart B Kinetic ProcessesKinetic Processes
tt (min)(min)
lnClnCtt
lnClnCtt = lnC = lnC00 - - KKeett
slope = - Kslope = - Kee
tt1/21/2 = 0.693 / K = 0.693 / Kee
VVdd = D / C = D / C00
Cl = VCl = Vdd × K × Kee
lnClnC00
slope = - Kslope = - Kee
First order kineticsFirst order kinetics
One compartment modelOne compartment model
Intravenous administrationIntravenous administration
5.5. Multiple dosing Multiple dosing
Steady state: 4Steady state: 4 ~~ 5 5 tt1/21/2
Varying according to dose and Varying according to dose and intervalsintervals
Part BPart B Kinetic ProcessesKinetic Processes
Same dose and different intervalsSame dose and different intervals
Different doses and same intervalDifferent doses and same interval
Same total doses and different intervalsSame total doses and different intervals
Same dose and same interval, but first Same dose and same interval, but first dose × 2dose × 2
C-T curves of drug after multiple dosing at same C-T curves of drug after multiple dosing at same interval and same doseinterval and same dose
Loading dose (DLoading dose (DLL)) DDLL = target C = target Cssss VVd ssd ss / F / F
Maintenance doseMaintenance dose raterate (DDm m )) DDmm == target Ctarget Cssss CL / FCL / F
Part BPart B Kinetic ProcessesKinetic Processes