bioequivalence in adv

Bioequivalence In Vitro-In VivoCorrelations

Study Design & Data Interpretationbased on the

Biopharmaceutic Classification System

Surang Judistprasert

Introduction

Oral Drug Product Administration Drug Activity

Dissolution Absorption Distribution Clearance (Metabolic / Renal) PK Profile in Plasma, Fluids, Tissues Clinical Efficacy & Adverse Events

Cmax ,Tmax , AUC

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Introduction

Bioavailability CFR ~ Assessed as “Rate” & “Extent” of Absorption Reality ~ Peak (Cmax) & Total (AUC) Exposure

Bioequivalence CFR ~ Equivalent “Rate” & “Extent” of Absorption Reality ~ Equivalent Peak (Cmax) & Total (AUC) Exposure

Concept of BE study

Probability of Bioequivalence Probability of IVIVC

As related to the Biopharmaceutics Classification System (BCS)

Mechanistic Variables

Mechanistic variables that complicate the establishment of BE or IVIVC Factors that result in bioavailability < 100% &

variability

Some can be controlled during drug product development ?

Understanding those not so easily controlled can help predict the probability of BE or IVIVC from in vitro data ?

Mechanistic Variables

Incomplete release of drug at site (formulation)

Insufficient drug in solution at site (substance)

First pass metabolism (variability)

Low g.i. permeability (variability)

Biopharmaceutics Classification SystemDrug Products

Solubility PermeabilityClass I High* HighClass II** Low HighClass III High* LowClass IV Low Low

* Highly-soluble substance in a rapidly-dissolving formulation ** If Do Low ~ Highest probability of In vitro / in vivo correlation

Biopharmaceutics Classification System

Highly Soluble Drug Substance Highest dose unit is soluble in 250mL or less between pH

1.0 & 7.5 Rapidly Dissolving Product

900mL media UPS Apparatus I (100rpm) or II (50rpm)

pH 1, 4.5, 6.8 85% in solution in 30min (15min to avoid F2)

Classification is theoretically based on Solubility of Drug substance Release from formulation into solution (Dissolution)

Biopharmaceutics Classification System

Highly Permeable Drug (Substance) Absolute Bioavailability ≳ 90% Mass Balance Recovery ≳ 90% In vitro methods (Caco-2 Cells)

Permeability (apparent) depends upon: Transport across GI wall Site of Absorption

Drug has to be in solution at the absorption site Drug has to be in contact with the site for adequate time

Biopharmaceutics Classification System

Solubility of Drug Substance

Highly Soluble Drug Substance High solubility (Highest dose unit dissolves in

initial gastric volume ~ 250mL) between pH 1.0 & 7.5

Low Solubility Drug Substance Low solubility (Highest dose unit will not dissolve

in initial gastric volume ~ 250mL) between pH 1.0 & 7.5

Biopharmaceutics Classification System

Release from Formulation( into solution )Rapidly Dissolving Product 900mL media

UPS Apparatus I (100rpm) or II (50rpm)pH 1, 4.5, 6.885% in solution in 30min (15min to avoid F2)

Biopharmaceutics Classification System

How to evaluate BCS drug?

• Class I – No 1st Pass ~ Bioequivalent• Class III & Class I + 1st Pass ~ Bioequivalent if

Powered Properly• Class II ~ Bioequivalent if dissolution data match at

pH 1, pH 4.5, Ph 6.8 (If 1st pass ~ Power Properly)• Class IV ~ Less predictableLess predictable

Predication

If a pharmaceutical formulation Immediately releases 100% of drug substance into solution

at the site of absorption & If GI membrane transport is not restricted

We might expect Rapid rate & optimal extent of absorption High Absolute Bioavialbility Short tmax

Predication

If a pharmaceutical formulation Slower release of drug substance into solution at the site of

absorption & If GI membrane transport is not restricted

We might expect in vivo dissolution to correlate with input (absorption) in vitro release to predict PK profile in vitro - in vivo correlation (IVIVC)

Predication

If two pharmaceutically equivalent formulations Demonstrate similar in vivo dissolution under all GI

conditions & If GI membrane transport is not restricted

We expect Similar concentration - time profiles at all GI membrane

surfaces & accordingly Similar overall rate & extent of absorption Bioequivalence

Predication

If two pharmaceutically equivalent formulations Demonstrate similar in vivo dissolution under all GI

conditions & If GI membrane transport is restricted

We expect Similar concentration - time profiles at all GI membrane

surfaces & accordingly Similar overall rate & extent of absorption Bioequivalence ???

Predication

If two pharmaceutically equivalent formulations Demonstrate similar in vivo dissolution under all GI

conditions & If GI membrane transport is restricted

We expect ~ Variability Similar concentration - time profiles at all GI membrane

surfaces & accordingly Similar overall rate & extent of absorption BioINequivalence ~ Unless study properly powered

Predication

If two pharmaceutically equivalent formulations Demonstrate similar in vivo dissolution under all GI

conditions & If GI membrane transport is not restricted ~ 1st Pass

We expect Similar concentration - time profiles at all GI membrane

surfaces & accordingly Similar overall rate & extent of absorption Bioequivalence ???

Predication

Bioequivalence ~ Failure Failed Product ~ Truly inequivalent Peak (Cmax) &

Total (AUC) Exposure Failed Study ~ Study Design Issues

Variability ~ Low Power of the ANOVA Low GI Permeability First Pass Metabolism

Bioequivalence Study Design

Sampling schedule Adequate data points around Cmax

Cover at least 3 half-lives from dose

Number of subjects Power of the ANOVA ≥ 80% Power ~ Probability of concluding

bioequivalence if treatments truly are BE

Potential Impact of Failed BE Testing

Phase I Food Effects Dose Proportionality Dose dumping from CR tablet broken at the score Drug-Drug Interactions

BE Studies SUPAC Site Transfers ANDA (Pilot & Pivotal BE Studies)

Designing a Successful BE Study using the

Biopharmaceutic Classification System

Hypothesis Based upon Experience

Class I drug products are bioequivalent First Pass Metabolism ~ Variability ~ Design Issues Certain excipients might alter g.i. permeability (???) Guidance permits BE waiver

Class II drug products are usually bioequivalent if

dissolution profiles match (pH 1, pH 4.5, pH 6.8) If first Pass Metabolism ~ Variability ~ Design Issues Certain excipients might alter g.i. permeability (???)

Designing a Successful BE Study using theBiopharmaceutic Classification System

Class III drug products are bioequivalent if study is powered account for variability Lower permeability = higher variability ~Design Issues If first Pass Metabolism ~ Variability ~ Design Issues Certain excipients alter g.i. permeability

Class IV drug products are often unpredictable