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Dermatopharmacokinetics (DPK)

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.

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Dermatopharmacokinetics (DPK)

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

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

  7. ln Dose Dose Model of Topical (Skin) Dosage Form Performance Clinical/PD Measurement Pharmacokinetic Measurement Dosage Form Performance DPK Drug In SC Site of Activity Therapeutic Effects Blood Systemic Effects Dosage Form Drug In Follicles 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 (www.fda.gov/cder/guidance/old098fn.pdf)

  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 • 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?

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