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Bioavailability and
Bioequivalence: General
concepts and overviewAriya Khunvichai, Ph.D.20 April 2007
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WHAT IS IT???
HOW IS IT???WHY IS IT???
REGULATION VERSUS PHARMACEUTICAL COMP.
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Facts Generic drugs are safe and effective
alternatives to brand name prescriptions
Generic drugs can help both consumers and
the government reduce the cost ofprescription drugs
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NDA vs. ANDA Review ProcessOriginal Drug
NDA Requirements
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Animal Studies
7. Clinical Studies
(Bioavailability/Bioequivalence)
Generic Drug
ANDA Requirements
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Bioequivalence Study (InVivo, In vitro)
Note: Generic drug applications are termed "abbreviated" because they are generallynot required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.Instead, generic applicants must scientifically demonstrate that their product is bioequivalent(i.e., performs in the same manner as the origina; drug).
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Generic Drug: Definition Same active ingredient (s)
Same route of administration
Same dosage form
Same strength
Same indications
Compares to reference listed drug (RLD)
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Bioequivalence (BE): Definitionthe absence of a significant difference in the rateand extent to which the active ingredient or activemoiety in pharmaceutical equivalents orpharmaceutical alternatives becomes available atthe site of drug action when administered at thesame molar dose under similar conditions inan appropriately designed study
.CDER U.S. Food & Drug Administration
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Bioequivalence
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0 5 10 15 20 25 30
Time (hours)
Concentration(ng/mL)
Test/Generic
Reference/Brand
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Goals of BEUltimate: Bioequivalence studies impact of changes tothe dosage form process after pivotal studies commenceto ensure product on the market is comparable tothat upon which the efficacy is based Establish that a new formulation has therapeutic equivalence in the rate
and extent of absorption to the reference drug product. Important for linking the commercial drug product to clinical trial
material at time of NDA Important for post-approval changes in the marketed drug formulation
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Scheme of Oral Dosage Form
Human Intestinal
Absorption (HIA)
Oral Bioavailability (%F)
1,2 Stability + Solubility3 Passive + Active Tr.
4 Pgp efflux + CYP 3A4
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Bioavailability The extent and rate at which its active moiety
is delivered from pharmaceutical form andbecomes available in the systemic circulation
(quantifies ABSORPTION = ?, Reasons for poor F)
Pharmacokineticsconc. vs time
Conc.(mg
/L)
Time (h)
0 25
0.0
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The true dose is not the drug swallowed;BUT is the drug available to exert its effect. Dissolution Absorption Survive metabolismMay have a drug with very low bioavailability Dosage form or drug may not dissolve readily Drug may not be readily pass across biological
membranes (i.e. be absorbed) Drug may be extensively metabolized during
absorption process (first-pass, gut wall, liver)Important component of overall variability Variable bioavailability may produce variable
exposure
Why do we care about BIOAVAILABILITY?
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Extent of absorption is reflected by AUC
Rate of absorption, ka, is reflected by TmaxBoth Rate and Extent of absorption affect CmaxLeads to 4 possible relative scenarios: (R) Rapid, (E) Complete Absorptionyields a short Tmax, high Cmax, high AUC (R) Rapid, (E) incomplete absorptionyields a short Tmax, low Cmax, low AUC (R) Slow, (E) complete absorptionyields a long Tmax, high Cmax, high AUC (R) Slow, (E) incomplete absorptionyields a long Tmax, low Cmax, low AUC
Rate versus Extent of Absorption
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Bioavailability IV???
Bench mark for bioequivalence
How to calculate?
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Clinical/PD Dose-Response
Bioequivalence studies assess in vivo impact of changes tothe dosage form/process after pivotal studies commence toensure product on the market is comparable to that uponwhich the efficacy is based
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Theophylline Concentration[mg/L]
F
EV1
(%
normal)
Mitenko & Ogilvie NEJM 289:600-3, 1973
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FDA Draft-Guidance for Industry (1997)Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products
New Dosage Form of a Previously Studied Drug
In some cases, modified release dosage forms may beapproved on the basis ofpharmacokinetic data linking
the new dosage form from a previously studiedimmediate-release dosage form. Because thepharmacokinetic patterns of controlled-release andimmediate release dosage forms are not identical, it is
generally important to have some understanding of therelationship of blood concentration to responsetoextrapolate to the new dosage form.
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Why do we need Bioequivalence studies? No clinical studies have been performed in
patients with the Generic Product to supportits Efficacy and Safety.
With data to support similar in vivoperformance (= Bioequivalence)Efficacy and Safety
data can be extrapolated from the InnovatorProduct to the Generic Product.
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Approaches to Determining BE (21 CFR320.24) In vivo measurement of active moiety in
biologic fluid
In vivopharmacodynamic comparison
(Topical Corticosteroid)
In vivo clinical comparison (Nasalsuspensions)
In vitro comparison(Nasal Solution, Topicalsolution, Oral solution)
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Study Design: Basic design consideration Minimize variability not attributable to
formulations
Minimize bias
To compare performance of two products!!!
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Study Designs Single-dose, two-way crossover, fasted Single-dose, two-way crossover, fed
Alternative Single-dose, parallel, fasted (Long half-life)
Single-dose, replicate design (Highly Variable
Drugs) Multiple-dose, two-way crossover, fasted
(Less Sensitive, non-linear kinetic)
Parallel or crossover?, Fasted or Fed?, Single or Multiple?, Replicate or nonreplicate?
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Duration of washout period for cross-overdesign
- should be approximately > 5 times the
plasma apparent terminal half-life
- However, should be adjusted accordingly fordrugs with complex kinetic model
Study Designs
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Sample size determination
- significant level ( = 0.05)
- 20% deviation from the reference product
- power > 80%
Sample time determination
- adequate data points around tmax
- 3 or more time of t1/2 to around AUC0-t = atleast 80% AUC0-inf
Study Designs
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Subjects? (Inclusion/exclusion criteria)
LABEL
Study Designs
(such as)Healthy subjects (male and female)18-55 years old, BMI = 18 25 kg/m2Non-smokers/without a history of alcohol or drug abuseMedical history/Clinical Lab test values must be within normal ranges
ContraindicationRefrain from the concomitants use of any medications or food interact withGI, renal, liver function from 28 days prior study Day1 through the safetyfollow up-visit.
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Study Design: Case 1Please conduct BE study of two brands of drug A in TabletInformation?
PK informationhalf-life = 10 hrsLow within subjects variability =~ 10-15%Drug mechanisms
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Statistical Analysis(Two one-sided Tests Procedure) AUC (Extent) and Cmax(Rate) Log
transformation- 90% Confidence Intervals (CI) of thedifference in Log (AUCt)Log (AUCR) must fit
between 80%-125%
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Statistical Analysis 80%-125% What does this mean?
Can there be a 46% difference?
What is a point estimate?
What is a confidence interval?
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Statistical analysis BE criteria
-Two one-sides tests procedure
Test (T) is notsignificantly less than reference
Reference (R) is not significantly less than test
Significant difference is 20% ( = 0.05 significance level)
T/R = 80/100 = 80%, or 100/80 =125%
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BE Results (90% CI)
T/R (%)80% 125%
Demonstrate BE
Fail to Demonstrate BE
Fail to Demonstrate BIE
Demonstrate BIE Demonstrate BIE
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Problems of 22 Crossover Design
Overparameterization
Carry-over effect is confounded
If carryover effect exists, the drug effectcannot be estimated correctly
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Screening ofVolunteers
ClinicalChemistry
ClinicalResearch
Implementation ofQUALITY SYSTEMS
Bioanalytical
Project
Management
Technology
Services
Pharmacokinetics& Biostatistics
Quality
Assurance
How to insured?
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In vivo BE InspectionsCovers clinical and analytical components
Study design Issues
Analytical method
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Bioanalytical Method ValidationMethod Validation should include
Accuracy
Precision
Sensitivity
Specificity
Recovery
Stability
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Accuracy
Closeness of determined valueto the true
Value
The acceptance criteria is mean value < 15%deviation from the true value.
At LOQ, 20% deviation is acceptable
Bioanalytical Method Validation
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Precision
The closeness of replicate determinations of
a sample byan assay
The acceptance criteria is < 15% CV, at
20% LOQ
Bioanalytical Method Validation
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Selectivity
Ability of the method to measure only what it
is intended to measure in the presence of
other components in the sample. Blank
samples of the biological matrix should be
tested for the interfering peak.
Bioanalytical Method Validation
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Recovery
The extraction efficiency of an analytical
process, reported as an percentage of the
known amount of an analyte. Recovery does
not have to be 100% but the extent of
recovery of internal standard and analyte
should be consistent.
Bioanalytical Method Validation
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Stability
During, sample collection , sample storage
and sample analysis process, the stability of
drug in matrix should be conducted
Bioanalytical Method Validation
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Thank you and Questions??
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Back up slides
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Statistical Method: Case 1
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Crossover Design 2x2 Crossover design A single-dose bioequivalence study is performed in
normal, healthy, adult volunteers.
18 subjects are hired (Male or Female?).
The subjects are randomly selected for each groupand the sequence of drug administration is randomlyassigned.
One-week washout periods Fasted or Fed?
Study Design: Case 1