# Presentation: 167779

## Dermatopharmacokinetics (DPK)

- Dale P. Conner, Pharm.D.
- Division of Bioequivalence
- Office of Generic Drugs, CDER, FDA

## Background

- Bioequivalence (BE)
- Current BE Methods for Topical Products

## 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/clinical 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

- Therapeutic
- Effect

- Dosage
- Form

- Gut Wall

- Drug in
- Solution

- Blood

- Site of
- Activity

- Pharmacokinetic Measurement

- Dosage Form Performance

- Clinical/PD Measurement

- ln Dose

- Dose

## Model of Topical (Skin) Dosage Form Performance

- Therapeutic
- Effects

- Dosage
- Form

- Site of
- Activity

- Drug
- In Tissue

- Blood

- Pharmacokinetic Measurement

- Dosage Form Performance

- Clinical/PD Measurement

- Systemic
- Effects

- DPK

## Model of Topical (Skin) Dosage Form Performance

- Therapeutic
- Effects

- Dosage
- Form

- Site of
- Activity

- Drug
- In SC

- Blood

- Pharmacokinetic Measurement

- Dosage Form Performance

- Clinical/PD Measurement

- Systemic
- Effects

- DPK

- Drug
- In Other

- Drug
- In Follicles

## Current Methods BE Methods for Topical Products

- BE Study with Clinical End-points
- Expensive
- Insensitive to differences in formulation performance
- BE Study with Pharmacodynamic End-points
- Limited to only a few classes of compounds (glucocorticoids)
- In Vitro Drug Release

## Clinical/PD Dose-Response

**Clinical/PD Response**

**Log Dose**

- Topical Dermatologic Corticosteroids: In Vivo Bioequivalence (www.fda.gov/cder/guidance/old098fn.pdf)

## Description of DPK Method

- Theory
- Pharmacokinetic approach applied to drug concentrations in stratum corneum (SC)
- Method
- Tape stripping is used to remove successive layers of SC after topical drug administration
- Uptake and elimination from SC are determined
- Differences in formulation performance (BE) are determined at the same time in the same individual

## History

- Workshops - AAPS/FDA
- May 1989
- March 1990
- December 1991
- FDA/Industry Conference: March 1992
- Advisory Committee (GDAC) - BE/DPK: April 1992
- Bio-International, Bad Homburg, Germany: May 1992

## History

- Workshop - AAPS/FDA on SUPAC and DPK: May 1993
- EUFEPS Nuremburg Conference: December 1995
- Bio-International, Tokyo, Japan: April 1996
- Workshop - AAPS/FDA on BE of Topicals: September 1996
- Trade Association Meetings: April 1997 and December 1997

## History

- Advisory Committee (ACPS) - BE/DPK: December 1997
- Advisory Committee (DODAC) - BE/DPK: March 1998
- Draft Guidance: June 18, 1998
- Joint Advisory Committee (ACPS and DODAC): October 23, 1998
- Expert Member and SGE meeting: July 30, 1999

## History

- Expert Members and Representatives from ACPS and DODAC: October 23, 1999
- Symposium - AAPS Annual Meeting: November 1, 2000
- Joint Advisory Committee (ACPS and DODAC): November 17, 2000

## Issues

- Is the DPK method an appropriate approach for establishing bioequivalence of topical drug products?
- Are results and conclusions derived from the DPK method consistent within and between laboratories?
- Can DPK methodology be established in any laboratory or CRO with a reasonable amount of time, effort and expense?