Dermatopharmacokinetics (DPK)

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Dermatopharmacokinetics (DPK)

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

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Background

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

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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/clinica
  l conditions

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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.

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Model of Oral Dosage Form Performance
Pharmacokinetic Measurement
Clinical/PD Measurement
Dosage Form Performance
Therapeutic Effect
Gut Wall
Drug in Solution
Blood
Site of Activity
Dosage Form
ln Dose
Dose
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Model of Topical (Skin) Dosage Form Performance
Pharmacokinetic Measurement
Clinical/PD Measurement
Dosage Form Performance
DPK
Therapeutic Effects
Site of Activity
Drug In Tissue
Blood
Systemic Effects
Dosage Form
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Model of Topical (Skin) Dosage Form Performance
Pharmacokinetic Measurement
Clinical/PD Measurement
Dosage Form Performance
DPK
Therapeutic Effects
Site of Activity
Drug In SC
Blood
Systemic Effects
Dosage Form
Drug In Follicles
Drug In Other
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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

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Clinical/PD Dose-Response
Clinical/PD Response
Log Dose
Topical Dermatologic Corticosteroids In Vivo
Bioequivalence (www.fda.gov/cder/guidance/old098fn
.pdf)
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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

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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

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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

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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

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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

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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?