Linear pharmacokinetics of penciclovir following administration of single oral doses of famciclovir 125, 250, 500 and 750 mg to healthy volunteers

Abstract

Twenty healthy male volunteers received single oral doses of famciclovir (125-750 mg), in a randomized, single-blind, crossover study. Plasma and urine concentrations of penciclovir and its 6-deoxy precursor, BRL 42359, were determined and penciclovir plasma concentration-time data submitted to model-independent pharmacokinetic analysis. Peak plasma concentrations of penciclovir were obtained at median times of 0.5-0.75 h after dosing. The areas under the concentration versus time curves (AUC) and the peak penciclovir concentration (Cmax) increased linearly with dose of famciclovir. Time to Cmax, elimination half-life, urinary recovery and renal clearance of penciclovir did not change with increasing dose. Famciclovir was excreted via the kidneys as penciclovir (60%) and BRL 42359 (5%), respectively. Famciclovir was well tolerated by all subjects with a low incidence of adverse effects. In conclusion, penciclovir thus displays linear pharmacokinetics in the anticipated therapeutic dose range of famciclovir.

Clinical and antiviral effect of a single oral dose of famciclovir administered to cats at intake to a shelter

“…Famciclovir was developed to increase bioavailability of its active metabolite, penciclovir, in humans (Pue et al, 1994). If administered to humans when symptoms commence, famciclovir can reduce the time to remission of clinical signs due to herpes simplex virus (HSV)-1 (Spruance et al, 2006) or HSV-2 (Aoki et al, 2006;Bodsworth et al, 2008).…”

“…However, the precise mechanism responsible for conversion of famciclovir to penciclovir is not known (Thomasy et al, 2012b). In a human study, maximum plasma penciclovir concentrations (Cmax) were achieved 30-45 min after administration of 125-750 mg famciclovir; neither time to Cmax or half-life were dose-dependent (Pue et al, 1994).…”

“…Penciclovir is converted to its active metabolite after three phosphorylation steps, the first being catalyzed by viral thymidine kinase in infected cells. The remaining two steps are catalyzed by cellular enzymes, resulting in relatively selective inhibition of viral DNA replication (Pue et al, 1994). In humans, the main route of penciclovir elimination following oral famciclovir administration is via the kidneys (Pue et al, 1994).…”

Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir

“…12,13 There are marked differences among species in the activity of this enzyme in liver cytosol; cats have markedly lower aldehyde oxidase activity, compared with rabbits, monkeys, humans, mice, cows, and dogs. 14,15 In humans, 16,17 dogs, and rats, 18 famciclovir is substantially absorbed and rapidly converted, primarily to penciclovir. Conversely, in cats, famciclovir is incompletely absorbed, and its metabolism to penciclovir becomes saturated at increasing doses, which leads to complex nonlinear PK.…”

Role of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of Purine-Related Drugs

“…Metabolism of famciclovir involves sequential hydrolysis of both acetyl groups to give 6-deoxypenciclovir which can be oxidized to penciclovir (Fig. 7); however, both in vivo and in vitro studies have also shown that penciclovir is the major metabolite of famciclovir metabolism (Pue & Benet, 1993;Pue et al, 1994;Rashidi et al, 1997). Although the oxidative step was initially attributed to XO, on the basis of studies performed with 6-deoxyaciclovir and a structural similarity between 6-deoxypenciclovir and guanine which is a substrate of XO (Harrell et al, 1993;Krenitsky et al, 1984;Vere Hodge et al, 1989), later studies demonstrated that AO is the major enzyme in oxidative conversion of famciclovir to penciclovir (Clarke et al, 1995;Rashidi et al, 1997).…”