This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citing articles on Web of Science (16)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Social Bookmarking   What's this?

Pharmacokinetic and Pharmacodynamic Dose-Response Studies in Humans

Lynn K. Pershing, PhD; Lyssa Lambert; E. David Wright, MD; Vinod P. Shah, PhD; Roger L. Williams, MD

Arch Dermatol. 1994;130(6):740-747.

Abstract
Background and Design
Effective topical drug therapy requires drug delivery into the skin to produce the desired pharmacodynamic response. For topical corticosteroids, the visual skin-blanching assay has been used to rank the potency of the corticosteroids and their overall efficacy. While vehicles have been shown to influence the resulting blanching response, the dose of drug applied has not always produced proportional differences in the blanching assay. The mechanism of the nonproportional pharmacodynamic response to the corticosteroid dose is unclear. We describe four methods for assessing the dose-response relationship of topical betamethasone dipropionate on the ventral forearm of six human subjects: duration, concentration, film thickness, and surface area. Drug uptake analysis in human stratum corneum and the resulting pharmacodynamic response, measured visually and with a chromameter, were performed with each method to quantify the dose-response relationship.

Results
Only the concentration and duration methods demonstrated an increase in mean drug uptake with increasing dose. The maximal mean pharmacodynamic response reflected the mean drug uptake with all four methods. Application conditions for maximal pharmacodynamic activity of topical betamethasone dipropionate in the skin include short duration of treatment (2 hours), a lower concentration than commercially marketed, and thin film thicknesses (1 to 5 µm).

Conclusion
A dose response can be produced by increasing the drug concentration or the duration of application time. Achievement of steady-state betamethasone dipropionate uptake into the stratum corneum was not commensurate with the maximal pharmacodynamic response. Very small amounts of this potent corticosteroid within the skin appear to maximize the receptor response to drug.

(Arch Dermatol. 1994;130:740-747)

Author Affiliations
From the Department of Medicine, Division of Dermatology, University of Utah School of Medicine, Salt Lake City (Drs Pershing and Wright and Ms Lambert); and the Food and Drug Administration, Office of Generic Drugs, Rockville, Md (Drs Shah and Williams).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?