Bioavailability and Bioequivalence: General concepts and overview

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Bioavailability and Bioequivalence General
concepts and overview

• Ariya Khunvichai, Ph.D.
• 20 April 2007

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WHAT IS IT???
WHY IS IT???
HOW 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 of prescription drugs

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NDA vs. ANDA Review Process

• Generic Drug
• ANDA Requirements
• Chemistry
• Manufacturing
• Controls
• Labeling
• Testing
• Bioequivalence Study (In Vivo, In vitro)

• Original Drug
• NDA Requirements
• Chemistry
• Manufacturing
• Controls
• Labeling
• Testing
• Animal Studies
• Clinical Studies
• (Bioavailability/Bioequivalence)

Note Generic drug applications are termed
"abbreviated" because they are generally not
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) Definition

• the absence of a significant difference in the
  rate
• and extent to which the active ingredient or
  active
• moiety in pharmaceutical equivalents or
• pharmaceutical alternatives becomes available at
• the site of drug action when administered at the
• same molar dose under similar conditions in
• an appropriately designed study.

CDER U.S. Food Drug Administration
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Bioequivalence
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Goals of BE

• Ultimate 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 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)
1,2 Stability Solubility 3 Passive Active
Tr. 4 Pgp efflux CYP 3A4
Oral Bioavailability (F)
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Bioavailability
(quantifies ABSORPTION ?, Reasons for poor F)

• The extent and rate at which its active moiety is
  delivered from pharmaceutical form and becomes
  available in the systemic circulation

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Why do we care about BIOAVAILABILITY?

• The true dose is not the drug swallowed
• BUT is the drug available to exert its effect.
• ?? Dissolution
• ?? Absorption
• ?? Survive metabolism
• May 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

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Rate versus Extent of Absorption

• Extent of absorption is reflected by AUC
• Rate of absorption, ka, is reflected by Tmax
• Both Rate and Extent of absorption affect Cmax
• Leads to 4 possible relative scenarios
• ?? (R) Rapid, (E) Complete Absorption
• yields a short Tmax, high Cmax, high AUC
• ?? (R) Rapid, (E) incomplete absorption
• yields a short Tmax, low Cmax, low AUC
• ?? (R) Slow, (E) complete absorption
• yields a long Tmax, high Cmax, high AUC
• ?? (R) Slow, (E) incomplete absorption
• yields a long Tmax, low Cmax, low AUC

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Bioavailability

• IV???
• Bench mark for bioequivalence
• How to calculate?

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Clinical/PD Dose-Response
FEV1 ( normal)
Theophylline Concentrationmg/L
Bioequivalence studies assess in vivo 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 efficacy is
based
Mitenko Ogilvie NEJM 289600-3, 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 be
approved on the basis of pharmacokinetic data
linking the new dosage form from a previously
studied immediate-release dosage form. Because
the pharmacokinetic patterns of
controlled-release and immediate release dosage
forms are not identical, it is generally
important to have some understanding of the
relationship of blood concentration to response
to extrapolate 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 support its
  Efficacy and Safety.
• With data to support similar in vivo performance
  ( Bioequivalence) Efficacy and Safety data can
  be extrapolated from the Innovator Product to the
  Generic Product.

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Approaches to Determining BE (21 CFR 320.24)

• In vivo measurement of active moiety in biologic
  fluid
• In vivo pharmacodynamic comparison (Topical
  Corticosteroid)
• In vivo clinical comparison (Nasal suspensions)
• In vitro comparison (Nasal Solution, Topical
  solution, 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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Study Designs

• Duration of washout period for cross-over design
• should be approximately gt 5 times the plasma
  apparent terminal half-life
• However, should be adjusted accordingly for drugs
  with complex kinetic model

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Study Designs

• Sample size determination
• significant level (a 0.05)
• 20 deviation from the reference product
• power gt 80
• Sample time determination
• adequate data points around tmax
• 3 or more time of t1/2 to around AUC0-t at
  least 80 AUC0-inf

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Study Designs

• Subjects? (Inclusion/exclusion criteria)
• LABEL

(such as) Healthy subjects (male and
female) 18-55 years old, BMI 18 25
kg/m2 Non-smokers/without a history of alcohol or
drug abuse Medical history/Clinical Lab test
values must be within normal ranges Contraindicati
on Refrain from the concomitants use of any
medications or food interact with GI, renal,
liver function from 28 days prior study Day1
through the safety follow up-visit.
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Study Design Case 1
Please conduct BE study of two brands of drug A
in Tablet
Information? PK information half-life 10
hrs Low 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 the difference
  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 not significantly less than
  reference
• Reference (R) is not significantly less than
  test
• Significant difference is 20 (a 0.05
  significance level)
• T/R 80/100 80, or 100/80 125

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BE Results (90 CI)
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Problems of 22 Crossover Design

• Overparameterization
• Carry-over effect is confounded
• If carryover effect exists, the drug effect
  cannot be estimated correctly

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How to insured?
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In vivo BE Inspections

• Covers clinical and analytical components
• Study design Issues
• Analytical method

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Bioanalytical Method Validation

• Method Validation should include
• Accuracy
• Precision
• Sensitivity
• Specificity
• Recovery
• Stability

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Bioanalytical Method Validation

• Accuracy
• Closeness of determined value to the true
• Value
• The acceptance criteria is mean value lt 15
  deviation from the true value.
• At LOQ, 20 deviation is acceptable

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Bioanalytical Method Validation

• Precision
• The closeness of replicate determinations of
• a sample by an assay
• The acceptance criteria is lt 15 CV, at
• 20 LOQ

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Bioanalytical Method Validation

• Sensitivity
• The limit of quantitation is the lowest
• concentration which can be measured with
• acceptable accuracy and precision

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Bioanalytical Method Validation

• 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.

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Bioanalytical Method Validation

• 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.

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Bioanalytical Method Validation

• Stability
• During, sample collection , sample storage
• and sample analysis process, the stability of
• drug in matrix should be conducted

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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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(No Transcript)
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Study Design Case 1

• 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 group
  and the sequence of drug administration is
  randomly assigned.
• One-week washout periods
• Fasted or Fed?