Influence of the treatment protocol upon the in vivo efficacy of cidofovir (HPMPC) and of acyclovir (ACV) formulations in topical treatment of cutaneous HSV‐1 infection in hairless mice

Abstract

In recent studies we found that the topical effectiveness of acyclovir (ACV) formulations was a single‐valued function of C*— the target site free drug concentration. The topical efficacy was the same when the therapy was initiated 0, 1, or 2 days after intracutaneous herpes simplex virus type‐1 (HSV‐1) inoculation in hairless mice. The purpose of the present study was to examine the hypothesis that the topical effectiveness of cidofovir (HPMPC) would not be a single valued function of C* and that it would be dependent upon when the therapy was initiated relative to the time of viral infection. Formulations of HPMPC and ACV in 95% DMSO as a vehicle were used. Hairless mice intracutaneously infected with HSV‐1 were used, and 20 µL of the test formulation was topically applied twice a day. In protocol A, the treatment was continued until the fourth day after virus inoculation, whereas in protocol B the treatment was terminated on the day of virus inoculation. Treatment was initiated on various days ranging from day −6 to day 4, and the lesions were scored on day 5. Treatment of ACV according to protocol A proved efficacious whether started as early as 6 days before virus inoculation or later, whereas the efficacy of ACV was annihilated if applied following protocol B. For HPMPC, on the other hand, the in vivo efficacies were found to be strongly dependent on how early the therapy was initiated, and significant efficacy was observed even when the treatment was terminated on the day of virus inoculation. This difference was attributed to the virus‐independent intracellular phos‐phorylation of HPMPC and slow clearance of its metabolites from the cell. It was also noted that, similar to ACV, for HPMPC the topical efficacy is likely to be a function of C* for a fixed protocol. However, unlike for ACV, for HPMPC the efficacy was not a single‐valued function of C*.