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

TherapeuticEffect

Dosage Form

Gut WallDrug in Solution

BloodSite of Activity

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurement

ln DoseDose

Model of Topical (Skin) Dosage Form Performance

TherapeuticEffects

Dosage Form

Site of Activity

DrugIn Tissue

Blood

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurement

ln Dose Dose

SystemicEffects

DPK

Model of Topical (Skin) Dosage Form Performance

TherapeuticEffects

Dosage Form

Site of Activity

DrugIn SC

Blood

Pharmacokinetic MeasurementDosage Form

Performance

Clinical/PD Measurement

ln Dose Dose

SystemicEffects

DPK

DrugIn Other

DrugIn 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

Cli

nic

al/P

D R

esp

onse

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?