An application of the [formula omitted] concept in predicting the topical efficacy of finite dose acyclovir in the treatment of cutaneous HSV-1 infections in hairless mice

Abstract

This study has examined C ∗ (and its temporal pattern) as a parameter for predicting topical antiviral efficacy of acyclovir (ACV) formulations in a recently developed hairless mouse model for the treatment of HSV-1 cutaneous infections. C ∗ referred to here is the free drug concentration at the target site, which is believed to be the basal cell layer of the epidermis. Two different topical ACV formulations, one available commercially (Zovirax 5% ointment) and the other prepared in our laboratories (3% ACV suspension) were investigated in a finite dose multiple dosing regimen (twice a day application) to simulate the clinical situation. C ∗ was calculated from in vitro flux data and information obtained from previous baseline studies. In vitro ACV flux determinations involved an in vivo-in vitro experimental design that was believed to approximate closely the actual in vivo antiviral treatment protocol. For the in vivo antiviral efficacy studies, a 1-day delayed (after virus inoculation) 4-day treatment protocol was implemented and the animals wore a Velcro jacket to protect the formulations from being removed during the drug application period. With Zovirax 5% ointment given 3 mg every 12 h, our results showed a 0% topical efficacy which was consistent with the C ∗ predictions. In the case of the laboratory prepared 3% ACV suspension, a dose of 2 μl was given every 12 h and our results showed a modest level (33–44%) of topical effectiveness, which was somewhat higher than predicted (0–25%) from C ∗ considerations. Also, in the efficacy studies (but not in the in vitro flux studies) with the laboratory prepared formulation, there were instances (20–33%) of severe skin irritation/damage noted at the end (day 5) of the experiments. Taking this into consideration, it is suggested that these studies represent a good correlation between predictions (C ∗) based on the in vitro data and the in vivo antiviral efficacy and validate the predictive value of this approach.