Estimation of the acyclovir concentration in the epidermis following transdermal drug delivery and its correlation with its antiviral efficacy

An experimental animal model for the study of the antiviral efficacy of acyclovir (ACV) in cutaneous HSV-1 infections utilizing controlled drug delivery with transdermal patches in hairless mice was developed previously. In this model, the extent of virus induced lesion development in skin areas underneath and/or adjacent to the areas covered by the dermal patches was used, in order to evaluate the topical and systemic antiviral efficacy of the patches. Both efficacies were expressed as a function of the drug delivery rate of the dermal patches. In the present study, the drug concentration in the epidermis/ dermis interface for both topical and systemic drug delivery was estimated. In the case of topical delivery, the drug concentration was deduced from the flux equation for ACV transport across Azone pretreated hairless mouse skin, assuming a permeability coefficient of the dermis corresponding to its full anatomical thickness. In the case of systemic delivery, the drug concentration in the water compartment of the epidermis was obtained from pharmacokinetic studies, which provided steady state blood levels of ACV following dermal patch application with hairless mice. For the equal topical and systemic antiviral efficacy values, the topical drug concentration was found to be 40 times higher than the systemic drug concentration. The reason for this difference was sought in the effect of the blood flow on the effective thickness of the dermis as a transport barrier in vivo. Estradiol was used as a probe in these studies. The transdermal permeation of estradiol and its main metabolite, estrone, was studied in vitro and in vivo using estradiol dermal patches. The experimentally obtained fluxes were fitted to a previously developed computational model for simultaneous transport and metabolism of estradiol in skin, and the effect of a reduced effective dermis thickness was tested. Different assumptions regarding the location of metabolic enzyme in the skin and the diffusivities in the basal and the keratinized epidermal layers were employed in this model, in order to explain the differences in the estrone back flux between the in vitro and the in vivo experiments. It was shown that a 40-fold reduction of the effective dermis thickness due to the blood flow in vivo was consistent with the experimental data.