# Presentation: 244501

## DermatopharmacokineticsPerspectives 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- Draft Guidance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								Expensive								Insensitive
- Pharmacodynamic		Applicable only to few classes					of compounds, e.g., Glucocorticoids
- Dermatopharmacokinetic	Feasible								Logical								Universally applicable
*In Vitro *drug release		Universally applicable						Signal 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 Products

**Dermatopharmacokinetics**

**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 Products

**Dermatopharmacokinetics 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-  Draft Guidance for comments (GGP-Level 1):  June 18, 1998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 Product**
**NDAs and ANDAs - In Vivo Bioavailability,**
**Bioequivalence, In Vitro Release,**
**and Associated Studies**

- Draft Guidance:	63 FR 33375, June 18, 1998
- 			Docket No. 98D-0388
- 			Level 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 Input_
- Research
- Workshops
- Advisory Committee
- Experts
- _DPK_

- Draft Guidance

****

****

****

- Comments
- Review
- Research
- Advisory Committee
- Experts

- Revision to Draft Guidance

- Final Guidance

****

****

- Guidance Process

## DermatopharmacokineticsWhat 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.

## DermatopharmacokineticsRelevance to clinical efficacy (data)

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

## Slide 11

## Tretinoin Research

**Products:**
**A.  **Retin-A gel, 0.025%, Ortho
**B.  **Tretinoin gel, 0.025%, Spear
**C.  **Avita tretinoin gel, 0.025%, Bertek
**Clinical Findings:**
- Retin-A gel = Tretinoin gel (A=B)
- Retin-A gel  Avita gel (AC), 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 active		Concentration/dose response relationship
- Same concentration of the active, but different vehicles	Significantly different formulations
**Can DPK predict the properties of a vehicle?**

## Slide 14

## Slide 15

## Slide 16

## DermatopharmacokineticsWhat 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.**

## DermatopharmacokineticsWhat are the applications of DPK ?

**Bioequivalence Assessment**
- 		Comparison of two products - T & R
**Bioavailability Assessment**
- 		BA of the product, application in line 		extension

## Topical Dermatological Drug Products

**Bioequivalence 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)**

## DermatopharmacokineticsBioequivalence 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 product**
**sameness under SUPAC-SS related changes**

## DermatopharmacokineticsWhat 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

## 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

## Dermatopharmacokinetics

**Disadvantages:**
- Requires validation of the stripping procedure
- Requires good sensitive analytical methodology and validation

## 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)

## 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)

## Slide 27

## Slide 28

## Slide 29

## 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

- 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**

## Dermatopharmacokinetics

*High Risk*	Vaginal		Different physiological
- 					  environment, mucous membrane
- 		Antiacne (Retinoid)    Follicular penetration
- 		Antiviral		Site of action not well defined
- 		Antibiotics
- 		Glucocorticoid
*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

## 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