1. Dermatopharmacokinetics (DPK)
Dale P. Conner, Pharm.D.
Division of Bioequivalence
Office of Generic Drugs, CDER, FDA

2. Background
Bioequivalence (BE)
Current BE Methods for Topical Products

3. 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

4. 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.

5. 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

6. Model of Topical (Skin) Dosage Form Performance
Clinical/PD Measurement
Pharmacokinetic Measurement
Dosage Form Performance
DPK
Dosage
Form
Drug
In Tissue
Site of
Activity
Therapeutic
Effects
Blood
Systemic
Effects
ln Dose
Dose

7. Model of Topical (Skin) Dosage Form Performance
Clinical/PD Measurement
Pharmacokinetic Measurement
Dosage Form Performance
DPK
Dosage
Form
Drug
In SC
Site of
Activity
Therapeutic
Effects
Blood
Systemic
Effects
Drug
In Follicles
ln Dose
Dose
Drug
In Other

8. 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

9. Clinical/PD Dose-Response
Clinical/PD Response
Log Dose
Topical Dermatologic Corticosteroids: In Vivo Bioequivalence (

10. 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

11. History Workshops - AAPS/FDA FDA/Industry Conference: March 1992
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

12. 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

13. 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

14. 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

15. 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?