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

1. 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 Drug in Solution Gut Wall Blood Site of Activity Therapeutic Effect Dosage Form ln Dose Dose

9. 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

10. 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

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 80-125%

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

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

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

16. 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

17. 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

18. 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