ASSESSMENT OF CORRELATION BETWEEN SKIN TARGET SITE FREE DRUG CONCENTRATION AND THE IN-VIVO TOPICAL ANTIVIRAL EFFICACY IN HAIRLESS MICE FOR (E)-5-(2-BROMOVINYL)-2'-DEOXYURIDINE AND ACYCLOVIR FORMULATIONS

Recently, we reported that the in vivo efficacy of acyclovir (ACV) for mulations was a single valued function of skin target site free drug c oncentration (C) irrespective of the formulation compositions. A long -term objective of this research has been to generalize the C concept using model drugs which are similar to as well as different from AGV in their mechanism of actions. (Bromovinyl)-deoxyuridine (BVDU) was se lected as a model drug based on the reported similarity in its mechani sm of action with ACV. The relationship between the C predictions and the in vivo efficacies for some topical formulations containing diffe rent concentrations (0.05-10%) of either AGV or BVDU in 95% DMSO as a vehicle with or without 5% Azone as skin permeation enhancer was exami ned. Hairless mice infected cutaneously with HSV-1 were used to quanti tatively estimate the in vivo topical antiviral efficacy. A finite dos e of the test antiviral formulation was applied twice a day for 4 days , starting the day after virus inoculation. On the fifth day, the lesi ons were scored and the efficacy values were calculated. For each form ulation, in vitro flux experiments were performed in an in vivo-in vit ro experimental design that closely approximated the in vivo study pro tocol. As was previously shown, with all ACV formulations, a good corr elation was found between the C predictions and the in vivo topical e fficacy. With the BVDU formulations, on the other hand, this was found not to be the case. BVDU formulations with 5% Atone were generally mu ch more effective than those without Atone at comparable C values. Th is finding is believed to be the first of its kind showing that skin ' 'permeation enhancers'' may enhance efficacy by more than simply incre asing skin permeation rates.