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

• 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

• 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”

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)

Introduction

• Other Drugs with no specific BA/BE guidance– Estrogens

– Testosterone

– Progesterone

– Calcitriol

– Ursidiol

– Insulin

– Human growth hormone

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

• 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

TherapeuticEffect

Dosage Form

Gut WallDrug in Solution

BloodSite of Activity

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurem

ent

ln DoseDose

Model of Oral Dosage Form Endogenous Drug Performance

TherapeuticEffect

Dosage Form

Gut WallDrug in Solution

BloodSite of Activity

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurem

ent

ln DoseDose

Body Production Feedback

Model of Oral Dosage Form Endogenous (KCl) Drug Performance

TherapeuticEffect

Dosage Form

Gut WallDrug in Solution

BloodSite of Activity

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurem

ent

ln DoseDose

Body Stores

Urine

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

Agenda

• Case Study I: Levothyroxine - Background– Results of a Study by Abbott Labs– Levothyroxine BA

• Case Study II: Potassium Chloride

• Summary

Summary

• BE is a test of the comparative performance of formulations– Release of the drug substance from the drug

product– Rate– Extent

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

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

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?