1. Dale P. Conner, Pharm.D. Division of Bioequivalence OGD, CDER, FDA
Bioavailability (BA) and Bioequivalence (BE) of Endogenous Substance Drug Products
Dale P. Conner, Pharm.D.
Division of Bioequivalence
OGD, CDER, FDA

2. 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.

3. 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”

4. 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)

5. Introduction Other Drugs with no specific BA/BE guidance Estrogens
Testosterone
Progesterone
Calcitriol
Ursidiol
Insulin
Human growth hormone

6. 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

7. 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.

8. Model of Oral Dosage Form Performance
Pharmacokinetic Measurement
Clinical/PD Measurement
Dosage Form Performance
Dosage
Form
Drug in
Solution
Gut Wall
Blood
Site of
Activity
Therapeutic
Effect
Dose
ln Dose

9. Model of Oral Dosage Form Endogenous Drug Performance
Body
Production
Pharmacokinetic Measurement
Clinical/PD Measurement
Dosage Form Performance
Feedback
Dosage
Form
Drug in
Solution
Gut Wall
Blood
Site of
Activity
Therapeutic
Effect
Dose
ln Dose

10. Model of Oral Dosage Form Endogenous (KCl) Drug Performance
Pharmacokinetic Measurement
Body
Stores
Clinical/PD Measurement
Dosage Form Performance
Urine
Dosage
Form
Drug in
Solution
Gut Wall
Blood
Site of
Activity
Therapeutic
Effect
Dose
ln Dose

11. 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 %

12. Issues with Endogenous Substance Bioavailability/Bioequivalence
Assay sensitivity
Endogenous baseline
Feedback inhibition of endogenous production
Circadian rhythm
Linear/non-linear pharmacokinetics

13. Agenda Case Study I: Levothyroxine - Background
Results of a Study by Abbott Labs
Levothyroxine BA
Case Study II: Potassium Chloride
Summary

15. Summary BE is a test of the comparative performance of formulations
Release of the drug substance from the drug product
Rate
Extent

16. Summary
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

17. Summary
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

18. Summary
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?