title: Correlation of in vivo topical efficacies with in vitro predictions using acyclovir formulations in the treatment of cutaneous HSV-1 infections in hairless mice: an evaluation of the predictive value of the C* concept.
abstract: The purpose of this study was to carry out an extensive examination of the C* concept for prediction of the topical antiviral efficacies of acyclovir (ACV) formulations in a hairless mouse model for the treatment of cutaneous herpes simplex virus type-1 (HSV-1) infections. This method is based on estimation of the free drug concentration at the target site (C*), which is presumed to be the basal cell layer of the epidermis. Five different formulations (containing 5% ACV) were examined in a finite dose multiple dosing regimen (twice a day application) to simulate the clinical situation. For determination of C*, in vitro ACV fluxes across the hairless mouse skin were measured in an in vivo-in vitro experimental design that approximated the in vivo antiviral treatment protocol. Then, the in vivo antiviral efficacies were measured using a 1-day delayed (after HSV-1 virus inoculation) 4-day treatment protocol. 10 microL/cm2 dose of ACV formulation was applied every 12 h for 4 days after which the lesions were scored and efficacies were calculated. Our results indicate that, over a wide range of efficacies, the predictions based on C* (estimated from the experimental fluxes) are in good agreement with the in vivo antiviral efficacies. These studies, therefore, support the validity of the C* concept for various ACV formulations and suggest that the C* approach has potential for future practical situations.
authors: Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City 84112, USA.
authors: P J
authors: PJ
authors: Patel
authors: A H
authors: AH
authors: Ghanem
authors: W I
authors: WI
authors: Higuchi
authors: V
authors: V
authors: Srinivasan
authors: E R
authors: ER
authors: Kern
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000627:therapeutic use*; D000287:Administration, Topical; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy*; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008812:Mice, Hairless
chemical_list: D000998:Antiviral Agents; D000212:Acyclovir