Pharmacokinetics of Penciclovir after Oral Administration of its Prodrug Famciclovir to Horses

Abstract

ABSTRACT. We investigated the pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses. Following an oral dose of famciclovir at 20 mg/kg, maximum plasma concentrations of penciclovir occurred between 0.75 and 1.5 hr (mean 0.94  0.38 hr) after dosing and were in the range 2.22 to 3.56 g/ml (mean 2.87  0.61 g/ml). The concentrations of penciclovir declined in a biphasic manner after the peak concentration was attained. The mean half-life of the rapid elimination phase was 1.73  0.34 hr whereas that of the slow elimination phase was 34.34  13.93 hr. These pharmacokinetic profiles observed were similar to those of another antiherpesvirus drug, acyclovir, previously reported in horses following oral dosing of its prodrug valacyclovir.KEY WORDS: equine, famciclovir, penciclovir, pharmacokinetics.J. Vet. Med. Sci. 72(3): 357-361, 2010 Equine herpesvirus type 1 (EHV-1) is a major causative agent of respiratory disease in horses and can also lead to abortion and neurological disease [1]. In particular, the recent increase in neurological EHV-1 outbreaks among horses in the U.S.A., the U.K. and Europe is of major concern to the horse industry worldwide, since affected animals often have a poor prognosis [7,8,[17][18][19][20]. The antiherpesvirus drug acyclovir has been used for the treatment of EHV-1-associated neurological disorders [13,20,36]. Oral administration is preferable to intravenous infusion during outbreaks, but pharmacokinetic studies have revealed that acyclovir given orally to horses is poorly bioavailable and reaches low plasma concentrations [4,15,35] that do not exceed the 50% effective concentration (EC 50 ) against EHV-1 strains, as determined by in vitro plaque reduction assay [16]. In contrast, oral administration of valacyclovir, the prodrug of acyclovir, achieves concentrations within the sensitivity range of EHV-1 [15,23]. Therefore, valacyclovir is now considered to be an attractive candidate for treatment of EHV-1-associated neurological disorders, even though its therapeutic efficacy has not been proven in a controlled study.Another antiherpesvirus drug, famciclovir, is the oral prodrug of penciclovir. Like acyclovir, penciclovir is a guanine analogue. It is phosphorylated to penciclovir monophosphate by the viral thymidine kinase, and then to penciclovir diphosphate and triphosphate by cellular enzymes in virusinfected cells [32,33]. Penciclovir triphosphate inhibits viral DNA synthesis through competitive inhibition of DNA polymerase; consequently, viral replication in herpesvirusinfected cells is inhibited, with no effect on DNA synthesis in uninfected cells [10,32]. However, like acyclovir, penciclovir is very poorly absorbed when administered orally to rodents [6,34] and humans [5]. Famciclovir is the diacetyl ester of 6-deoxy penciclovir and has good bioavailability in humans [5,12,24,34]. After oral administration, famciclovir is converted to penciclovir through di-deacetylation in the intestinal wall and liver and oxidation in the liver [3...

Pharmacokinetics of ganciclovir and valganciclovir in the adult horse

“…administration were best described by a three‐compartment model with an elimination phase half‐life of 72 ± 9 h. This prolonged elimination half‐life of ganciclovir in horses was in contrast to that reported in other species, where average elimination half‐lives were 5 h or less (Serabe et al ., ; Winston et al ., ). Although the disposition of ganciclovir in horses differed considerably from that of other mammalian species, it was consistent with the pharmacokinetics of the related nucleoside analogs acyclovir and penciclovir in horses, where the elimination half‐life was similarly prolonged (Garré et al ., ; Maxwell et al ., ; Tsujimura et al ., ). Thus, it appears that horses may handle the nucleoside analogs in a fundamentally different manner than do most other species, with a prolonged terminal phase that has been posited to represent a deep compartment that slowly returns drug to circulation (Maxwell et al ., ).…”

“…dosing. Pharmacokinetic studies of antiviral drugs such as acyclovir, valacyclovir, and famciclovir have consistently reported prolonged elimination half‐lives in the horse (Garré et al ., ; Maxwell et al ., ; Tsujimura et al ., ). This is in contrast to studies examining the pharmacokinetics of nucleoside analogs in most other species, where the elimination half‐lives are considerably shorter.…”

Third International Havemeyer Workshop on Equine Herpesvirus type 1

“…Such methods are required to type and select horses easily for future immunological studies and vaccine trials. Metaphylactic administration of small interfering RNA against EHV‐1 gB and the origin‐binding helicase, immediately before and after experimental EHV‐1 infection of horses, resulted in lessening of neurological signs and reduced frequency of euthanasia in one study [62]; however, these results could not be corroborated (Gillian Perkins, Cornell University). Prophylactic treatment of horses in the early stages of experimentally induced EHM disease with gancyclovir resulted in slower progression to ataxia, even when the drug administration was delayed to 4–6 days post experimental infection. However, identifying the stage of infection in field cases may be problematic [63–67].…”

“…Prophylactic treatment of horses in the early stages of experimentally induced EHM disease with gancyclovir resulted in slower progression to ataxia, even when the drug administration was delayed to 4–6 days post experimental infection. However, identifying the stage of infection in field cases may be problematic [63–67].…”

Equine Herpesvirus-1 Infection, Clinical Features, Treatment and Control

“…Oral administration of famciclovir the prodrug of penciclovir to horses at 20 mg/kg resulted in maximum plasma concentrations occurred between 0.75 and 1.5 hr. (Tsujimura et al, 2010) but penciclovir is very poorly absorbed when administered orally.…”