RELATIONSHIP OF SKIN TARGET SITE FREE DRUG CONCENTRATION (C-ASTERISK)TO THE IN-VIVO EFFICACY - AN EXTENSIVE EVALUATION OF THE PREDICTIVE VALUE OF THE CC CONCEPT USING ACYCLOVIR AS A MODEL-DRUG

For the past few years, our laboratory has been involved in the develo pment of a novel approach for predicting topical in vivo efficacy base d on the estimation of skin target site free drug concentration (C) f rom in vitro flux data. We have used acyclovir (ACV) as a model drug i n the treatment of cutaneous herpes simplex virus type 1 infections in hairless mice. The goal of this study was to rigorously evaluate the applicability of this approach over the entire range of topical effica cy (i.e., from 0 to 100%). We employed a variety of ACV formulations d iffering in solvent compositions, enhancers, and excipients (and there fore in their efficacies) to achieve this goal. The C values were est imated from the in vitro flux data obtained in an in vivo-in vitro exp erimental design that closely approximated the in vivo treatment proto col. For the in vivo antiviral efficacy studies, a finite dose of ACV formulation was applied twice a day, beginning the day after virus ino culation, for 4 days. The lesions were scored on the fifth day, and th e efficacies were calculated as described earlier.(1) Our results indi cate that, for a variety of formulations over a wide range of efficaci es, the predictions based on C are in good agreement with the observe d in vivo efficacies. These findings strongly demonstrate the predicti ve value of C over the entire range of topical efficacy, thereby furt her strengthening its potential for future studies. The findings also indicate that although the excipients in a formulation may alter the r ate and extent of available drug at the target site, in these cases, t hey do not seem to have any effect on the in vivo potency of the drug.