dermatopharmacokinetics perspectives from bioequivalence viewpoint historical development of...
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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
Center for Drug Evaluation and Research
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– Methods to Assess BE of Topical Drug Products– History of DPK– Draft Guidance– On Going studies in Utah
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Methods to Document Bioequivalence
•Clinical DifficultExpensiveInsensitive
•Pharmacodynamic Applicable only to few classesof compounds, e.g., Glucocorticoids
•Dermatopharmacokinetic FeasibleLogicalUniversally applicable
•In Vitro drug release Universally applicableSignal of possible inequivalence
Center for Drug Evaluation and Research
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
Center for Drug Evaluation and Research
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
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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• Advisory Committee (ACPS) - BE/DPK: December 1997• Advisory Committee meeting (DODAC) - BE/DPK: March 1998• Draft Guidance for comments (GGP-Level 1): June 18, 1998• Joint Advisory Committee (ACPS and DODAC): October 23, 1998• Expert Member + SGE meeting: July 30, 1999• Expert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
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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
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Defining and Understanding the problem & issues
Scientific InputResearchWorkshopsAdvisory CommitteeExpertsDPK
Draft Guidance
CommentsReviewResearchAdvisory CommitteeExperts
Revision to Draft Guidance
Final Guidance
Guidance Process
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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.
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Dermatopharmacokinetics
Relevance to clinical efficacy (data)
Can DPK differentiate products with same concentration of active but with different clinical efficacy?
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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
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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?
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Center for Drug Evaluation and Research
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.
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DermatopharmacokineticsWhat are the applications of DPK ?
– Bioequivalence Assessment
Comparison of two products - T & R
– Bioavailability Assessment
BA of the product, application in line
extension
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Topical Dermatological Drug ProductsBioequivalence Determination
Dermatopharmacokinetics
•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)
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DermatopharmacokineticsBioequivalence Assessment
Comparison of T and R Products - BE Documentation
– Dermatopharmacokinetics
– Q1 and Q2
– In vitro release
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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
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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
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Dermatopharmacokinetics
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
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Dermatopharmacokinetics
Disadvantages:
– Requires validation of the stripping procedure
– Requires good sensitive analytical methodology
and validation
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Dermatopharmacokinetics
Drug 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)
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Dermatopharmacokinetics
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)
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Center for Drug Evaluation and Research
• 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
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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
Dermatopharmacokinetics
Center for Drug Evaluation and Research
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
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Conclusions
For 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