Assessing Topical Bioavailability and Bioequivalence: A Comparison of the In vitro Permeation Test and the Vasoconstrictor Assay

Abstract

To compare the sensitivity of a pharmacokinetic assay, the in vitro permeation test (IVPT), with that of a pharmacodynamic assay, the human skin blanching or vasoconstrictor (VC) assay, in assessing the relative bioavailability of topical clobetasol propionate products. The percutaneous absorption of clobetasol propionate from five commercial products was measured in vitro using cryopreserved human skin. The pharmacodynamic potency of the same five products was also assessed in vivo using the VC assay, the surrogate method by which regulatory authorities in the United States establish the bioequivalence of generic topical glucocorticoid products. IVPT found total clobetasol absorption varying ten-fold from highest to lowest product, whereas the VC assay found this same difference was less than two-fold. The coefficient of variation ranged from 78 to 126% in the VC assay, but only 30-43% for IVPT. Statistically, IVPT could separate the 5 products into three groups: 1) ointment, 2) cream and gel, 3) emollient cream and solution). Due to its greater variability as well as saturation of the pharmacodynamic response at higher flux levels, the VC assay found all products except the solution to be equipotent. IVPT was found to be substantially more sensitive and less variable than the VC assay for assessing clobetasol bioavailability.