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Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products. Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA. Objective . Awareness topic discussion Provide information to ACPS on the challenges for BA/BE assessment of endogenous drugs

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bioavailability ba and bioequivalence be of endogenous substance drug products

Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products

Dale P. Conner, Pharm.D.

Division of Bioequivalence

OGD, CDER, FDA

objective
Objective
  • Awareness topic discussion
  • Provide information to ACPS on the challenges for BA/BE assessment of endogenous drugs
  • More detailed discussion is planned for the future
    • Biopharmaceutics Subcommittee meeting
    • ACPS meeting
  • At this meeting FDA seeks ACPS recommendations on how to develop the information needed to enhance the science in this area.
introduction
Introduction
  • BA and BE of endogenous substance drug products need special considerations
  • Not addressed in the general BA/BE guidance, “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations”
introduction4
Introduction
  • Specific recommendations
    • Potassium Chloride Modified-Release Tablets and Capsules: In Vivo Bioequivalence and In Vitro Dissolution Testing (Draft - Issued 8/2002, Posted 8/6/2002)
    • Levothyroxine Sodium Tablets - In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing (Issued 2/2001, Posted 3/8/2001)
introduction5
Introduction
  • Other Drugs with no specific BA/BE guidance
    • Estrogens
    • Testosterone
    • Progesterone
    • Calcitriol
    • Ursidiol
    • Insulin
    • Human growth hormone
definition of bioequivalence
Definition of Bioequivalence
  • Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions
purpose of be
Purpose of BE
  • Therapeutic equivalence (TE)
  • Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring.
  • The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner.
model of oral dosage form performance
Model of Oral Dosage Form Performance

Pharmacokinetic Measurement

Clinical/PD Measurement

Dosage Form Performance

Drug in

Solution

Gut Wall

Blood

Site of

Activity

Therapeutic

Effect

Dosage

Form

ln Dose

Dose

model of oral dosage form endogenous drug performance
Model of Oral Dosage Form Endogenous Drug Performance

Body

Production

Pharmacokinetic Measurement

Clinical/PD Measurement

Dosage Form Performance

Feedback

Drug in

Solution

Gut Wall

Blood

Site of

Activity

Therapeutic

Effect

Dosage

Form

ln Dose

Dose

model of oral dosage form endogenous kcl drug performance
Model of Oral Dosage Form Endogenous (KCl) Drug Performance

Pharmacokinetic Measurement

Body

Stores

Clinical/PD Measurement

Dosage Form Performance

Urine

Drug in

Solution

Gut Wall

Blood

Site of

Activity

Therapeutic

Effect

Dosage

Form

ln Dose

Dose

statistical analysis two one sided tests procedure
Statistical Analysis (Two One-sided Tests Procedure)
  • AUC and Cmax
  • Log-transformed data
  • ANOVA
    • Model: Period, Sequence, Subject(Seq), Treatment
  • 90% Confidence Intervals (CI) must fit between 80-125%
issues with endogenous substance bioavailability bioequivalence
Assay sensitivity

Endogenous baseline

Feedback inhibition of endogenous production

Circadian rhythm

Linear/non-linear pharmacokinetics

Issues with Endogenous Substance Bioavailability/Bioequivalence
agenda
Case Study I: Levothyroxine - Background

Results of a Study by Abbott Labs

Levothyroxine BA

Case Study II: Potassium Chloride

Summary

Agenda
summary
BE is a test of the comparative performance of formulations

Release of the drug substance from the drug product

Rate

Extent

Summary
summary16
Baseline correction of data may be necessary to ensure a sensitive method for the demonstration of BE

Characteristics of baseline

Methods for correction

Magnitude of baseline in relationship to the values after treatment

Summary
summary17
Endogenous baselines that change due to the administration of exogenous drug substance present a technical challenge to the demonstration of BA and BE

Circadian patterns

Feedback

Pharmacokinetics

Summary
summary18
Can a decision tree be developed that will guide sponsors in the correct BA and BE studies to be done for other endogenous drug products?Summary