Evaluation of In Vivo Bioequivalence Methodology for Topical Clobetasol 17-Propionate Based on Pharmacodynamic Modeling Using Chinese Skin

Abstract

The United States Food and Drug Administration recommends pilot dose duration–response and pivotal bioequivalence studies to be conducted using reflectance colorimetry for assessment of the in vivo bioequivalence of topical dermatologic corticosteroids. The major objectives of the present studies were to examine the applicability of the standardized pharmacodynamic modeling‐based methodology to super‐potent clobetasol 17‐propionate (CP) in the Chinese population and to evaluate the bioequivalence of two generic ointments and four generic creams containing 0.05% (w/w) CP with respect to Dermovate formulations using such methodology. In the pilot dose duration–response study, although the Emax model (where Emax is the maximum fitted value of AUEC, which is the area under the baseline‐corrected, untreated control‐site‐corrected a* scale data from 0 to 24h after drug removal) did not provide acceptable model fits, Emax parameter estimates of −38.97 ± 3.62 and −41.89 ± 11.28 a*‐scale · h, and ED50 (dose duration required to achieve 50% of the fitted Emax value) estimates of 0.40 ± 0.37 and 0.42 ± 0.16h were obtained for Dermovate ointment and cream, respectively, by population analyses. The estimates for the two formulations were not statistically different, so in vivo bioequivalence studies were conducted at an ED50dose duration of ∼0.5h for both Dermovate formulations. The results demonstrated that one generic ointment was bioequivalent to Dermovate, whereas the other was not. None of the generic creams were shown to be bioequivalent to Dermovate cream. The in vivo bioequivalence data from the vasoconstriction assay were linearly correlated with stratum corneum uptake of the drug at the same dose duration until the maximal vasoconstriction response was achieved. The studies illustrated the applicability of the standardized pharmacodynamic modeling‐based methodology in detecting the product differences between a variety of generic 0.05% CP formulations and reference Dermovate formulations in Chinese skin. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:207–217, 2004