vinod p. shah, ph.d. chair, topical drug products wg ops/cder/fda

Center for Drug Evaluation and Research

DermatopharmacokineticsPerspectives from Bioequivalence

Viewpoint

Historical Development of Dermatopharmacokinetics

and Overview of the Guidance

Vinod P. Shah, Ph.D.Chair, Topical Drug Products WG

OPS/CDER/FDA


Historical Development of Dermatopharmacokinetics and

Overview of the Guidance

– Methods to Assess BE of Topical Drug Products– History of DPK– Draft Guidance– On Going studies in Utah


Methods to Document Bioequivalence•Clinical Difficult

ExpensiveInsensitive

•Pharmacodynamic Applicable only to few classesof compounds, e.g., Glucocorticoids

•Dermatopharmacokinetic FeasibleLogicalUniversally applicable

•In Vitro drug release Universally applicableSignal of possible inequivalence


Dermatopharmacokinetics

– Pharmacokinetics applied to drug concentration measurements in stratum corneum (SC) is termed DPK

– Tape stripping method is a tool to measure drug concentration in SC and to determine drug uptake and elimination (disappearance) from SC


Topical Dermatological Drug ProductsDermatopharmacokinetics

Chronology:

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


Topical Dermatological Drug ProductsDermatopharmacokinetics cont’d)

Chronology (cont’d):

• Advisory Committee (ACPS) - BE/DPK: December 1997• Advisory Committee meeting (DODAC) - BE/DPK: March 1998• Draft Guidance for comments (GGP-Level 1): June 18, 1998• Joint Advisory Committee (ACPS and DODAC): October 23, 1998• Expert Member + SGE meeting: July 30, 1999• Expert Members + Representatives from ACPS+DODAC:

October 23, 1999• Symposium: AAPS - Annual Meeting - November 1, 2000• Joint Advisory Committee (ACPS and DODAC):

November 17, 2000


Guidance for Industry

Topical Dermatological Drug ProductNDAs and ANDAs - In Vivo Bioavailability,

Bioequivalence, In Vitro Release,and Associated Studies

Draft Guidance: 63 FR 33375, June 18, 1998Docket No. 98D-0388Level 1 document, consistent with FDA’s good guidance practices (62 FR 8961, February 17, 1997)Comments by August 17, 1998

On Internet: http://www.fda.gov/cder/guidance


Defining and Understanding the problem & issues

Scientific InputResearchWorkshopsAdvisory CommitteeExpertsDPK

Draft Guidance

CommentsReviewResearchAdvisory CommitteeExperts

Revision to Draft Guidance

Final Guidance

Guidance Process


DermatopharmacokineticsWhat is needed to have a confidence in DPK?

• Relevance to clinical efficacy (data)• Ability of DPK to differentiate between formulations

– Can DPK predict the properties of a vehicle?• Reliability and reproducibility of the method.


DermatopharmacokineticsRelevance to clinical efficacy (data)

Can DPK differentiate products with same concentration of active but with different clinical efficacy?


Tretinoin Research

Products:A. Retin-A gel, 0.025%, OrthoB. Tretinoin gel, 0.025%, SpearC. Avita tretinoin gel, 0.025%, Bertek

Clinical Findings:Retin-A gel = Tretinoin gel (A=B)Retin-A gel Avita gel (AC), but Avita gel is effective

DPK Research: To confirm and validate Clinical Findings A=B A C


Dermatopharmacokinetics Can DPK differentiate between formulations?

Same vehicle, but different concentration of activeConcentration/dose response relationship

Same concentration of the active, but different vehiclesSignificantly different formulations

Can DPK predict the properties of a vehicle?


DermatopharmacokineticsWhat is needed to have a confidence in DPK?

• Relevance to clinical efficacy (data)- Can DPK differentiate products with same concentration of active but

with different clinical efficacy?

• Ability of DPK to differentiate between formulations– Same vehicle, but different concentration of active

Concentration/dose response relationship– Same concentration of the active, but different vehicles

Significantly different formulations?

• Can DPK predict the properties of a vehicle?• Reliability and reproducibility of the method.


DermatopharmacokineticsWhat are the applications of DPK ?

– Bioequivalence AssessmentComparison of two products - T & R

– Bioavailability AssessmentBA of the product, application in line

extension


Topical Dermatological Drug ProductsBioequivalence Determination


•Same % of active drug•Same route of administration - application•Same dosage form category, i.e.,

- cream vs. cream- ointment vs. ointment- gel vs. gel

•Generally qualitatively (Q1) same ingredients and quantitatively (Q2) similar composition (5%)

Ref: 21 CFR 314.94(a)(9)(v)


DermatopharmacokineticsBioequivalence Assessment

Comparison of T and R Products - BE Documentation

– Dermatopharmacokinetics

– Q1 and Q2

– In vitro release


In Vitro Release

In vitro release can differentiate between:- Different formulations- Two products manufactured differently- Products containing different particle size of the

actives

In vitro release test is used to assure productsameness under SUPAC-SS related changes


DermatopharmacokineticsWhat is needed to accept DPK?

– Validated tape stripping (skin stripping) procedure– Validated analytical methodology– Mass balance information/study data– Pilot study– Pivotal BE study– DPK data meeting 90% CI, and BE limits of 80-125% for AUC and Cmax



Advantages:

– Noninvasive procedure– Good dose response effect– Can differentiate significantly different formulations– Measures drug concentration in the vicinity of the site of

action in the skin– It is sensitive, reliable, reproducible and cost effective – Is applicable to all topical dermatological drug products



Disadvantages:

– Requires validation of the stripping procedure

– Requires good sensitive analytical methodology and validation


DermatopharmacokineticsDrug Uptake in SC and Drug Elimination from SC: SC Stripping Procedure

•Apply the Test and Reference drug products concurrently at multiple sites

•After X hours, clean the area 3 times lightly with tissue•Apply the adhesive tape (e.g., Transpore or Cuderm) with uniform

pressure, remove and discard the first stripping•Apply, remove and collect nine successive tapestrippings (at the

same spot) - extract the drug and determine the concentration using appropriate validated analytical method

•Express results as amount per surface area (ng/sq. cm)



Drug Uptake and Elimination:

Each application site yields a single drug concentration in SC

Drug uptake in SC (e.g., after 0.25, 05, 1 and 3 hours)

Drug elimination from SC (e.g., 3, 4, 6, 8 and 24 hours)


• Applicable to all topical drug products (including vaginal drug products, retinoids)

• Applicable to generic drug products with Q1 and Q2 ( 10%)

Changes Made• Applicable to retinoid and other products• Not applicable to vaginal drug products• Q1 and Q2 (5%)• In vitro release test

Draft Guidance


Therapeutic Class Comments

High Risk Vaginal Different physiological environment, mucous membrane

Antiacne (Retinoid) Follicular penetrationAntiviral Site of action not well definedAntibioticsGlucocorticoid

Low Risk Antifungal Close to site of action



Topical Dermatological Drug Products

Bioequivalence Determination

•Primary means to document BE- Dermatopharmacokinetic Data

•Supportive Information- In vitro release- Particle size distribution of active

drug substance


ConclusionsFor Bioequivalence Determination:

- DPK is a reliable, reproducible and relevant method to document BE between T and R drug products

- DPK is applicable to all topical dermatological drug products, and is cost effective

vinod p. shah, ph.d. chair, topical drug products wg ops/cder/fda

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