# Presentation: 781962

## Time-dependent concentrations in skin strippings and follicles

_**Issues - SC Surrogate For Target Site**_

- (Schaefer, H. and Redelmeir, T.E. (eds) Skin Barrier, Principles of Percutaneous Absorption, Kruger Publishers, p.198, 1996)

**Stratum corneum concentrations do not predict follicular concentrations. DPK cannot be used to assess BA/BE for follicularly delivered drugs.**

## Acyclovir in orthotopically grafted human skin on nude mice

- Despite the higher levels of ACV in skin (11-57) with topical applications,  clinically, orally administered drug is significantly more effective than topically administered drug. (Spruance et al. J. Infec. Disease, 163:728,1991)
**This poor correlation between stratum corneum concentrations and clinical effectiveness indicates that in general stratum corneum concentration kinetics may not represent the kinetics of the drug at the target site (epidermal-dermal junction in this case).**

_**Issues - SC Surrogate For Target Site (cont.)**_

- (Parry et al. J. Invest. Dermatol. 98:856,1992)

- (H.J. Weigmann et al. Skin Pharmacol Appl Skin Physiol 12:46, 1999)
- DPK data show difference between *Temovate* Cream and *Temovate-E* Cream.
- However, Glaxo reports comparable clinical efficacy between *Temovate* Cream and *Temovate-E* Cream and there is no difference in vasoconstriction (N=30) between these products.
**Labeling classifies both products as super high potency ****(PDR, 54:1278 - 1281, 2000).**

## Issues - Clinical Relevance (cont.)

*Temovate* (cont.)
- Differences in DPK between products may be due to issues such as:
-  **18-69% of applied dose recovered in SC strips in this study may represent unabsorbed drug and questions validity of study.**
**Spreading of the emollient cream beyond the application site diminishes amount recovered**.

## Correlation between Blanching and SC drug content is poor (R = 0.6) and is not statistically significant.
Diprosone lotion (DSL) and Diprolene ointment (DLO) gave similar SC concentrations.  Literature suggests DSL is Category 5 and DLO is Category 1 in clinical potency ( R. B. Stoughton, Annu. Rev. Pharm. Tox. 29:55, 1989). Thus, no correlation between clinical efficacy and SC concentrations.
Tape strips 2-11 had 38-92.7% of applied dose, indicating contamination of strips with residual drug on surface, rather than drug penetrated.

**Diprosone lotion (DSL) and Diprolene ointment (DLO) gave similar SC concentrations.  Literature suggests DSL is Category 5 and DLO is Category 1 in clinical potency ****( R. B. Stoughton, Annu. Rev. Pharm. Tox. 29:55, 1989).**** Thus, no correlation between clinical efficacy and SC concentrations**.
**Tape strips 2-11 had 38-92.7% of applied dose, indicating contamination of strips with residual drug on surface, rather than drug penetrated**.

## Future Studies 

**A staged approach:**
- Critical parameters of method must be identified, evaluated and formally validated.
- Proposed surrogate needs to be demonstrated to be relevant to target site.
- DPK results must be correlated to clinical outcomes.
- DPK then to be tested in specific therapeutic classes, different target sites in skin, different delivery systems.

## Future Studies (cont.)

**Critical study elements:**
- Blinded within-subject comparison, **multicenter.**
- Treatment groups: RLD, Test drug bioequivalent, Test drug non-bioequivalent, vehicle.
- Clinical relevant **dose **
-    **2 to 3 mg/ cm****2**
**Data from these studies must include mass balance** .

## Future Studies (cont.)

- Clinical Studies to determine whether **a relationship between SC concentration and systemic exposure (BA) exists,** as indicated in Dr. Rougier’s findings in rodents, and whether this relationship can also apply to drugs with varying physicochemical properties (oil soluble, large and small molecules).
- Study to compare DPK in **normal skin to diseased skin and different body sites.**

## Conclusions

- DPK is a research tool that has not been validated or shown to be correlated  to clinical efficacy and systemic safety
- PhRMA wishes to participate on  any Expert Panel or committee for this topic that is established by the Advisory Committee for Pharmaceutical Science or  Dermatology and Ophthalmic Advisory Committee.