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

Abstract

TitlePharmacokinetic modeling of penciclovir and brl42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir OBJECTIVESTo determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized. ANIMALS7 male domestic shorthair cats. PROCEDURESIn a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK-PD) indices were determined for penciclovir and compared among all dosage regimens. RESULTSCompared with penciclovir concentrations, BRL42359 concentrations were 5-to 11-fold greater in plasma and 4-to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens. CONCLUSIONS AND CLINICAL RELEVANCEIn cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus. (Am J Vet Res 2016;77:833-845)

A review of antiviral drugs and other compounds with activity against feline herpesvirus type 1

“…Famciclovir pharmacokinetics in the cat are extremely complex and nonlinear (i.e., doubling of famciclovir dose does not lead to doubling of plasma penciclovir concentration) presumably due to saturation of the hepatic oxidase . As a result, very high plasma concentrations of BRL42359 accumulate in the cat . Fortunately, this compound demonstrates very little cytotoxicity in vitro .…”

“…The inactive metabolite BRL 42359 is then oxidized by a hepatic aldehyde oxidase to the active antiviral compound, penciclovir, which is ultimately excreted in feces and urine. Based upon famciclovir, BRL 42359 and penciclovir concentrations in feline plasma following oral administration of famciclovir, similar steps likely occur in cats . Anatomic images courtesy of www.MedicalGraphics.de (license # CC BY ‐ ND 3.0 DE ).…”

Therapie des akuten viralen Katzenschnupfens

“…Famciclovir (90 mg/kg alle 12 Stunden p. o. bis zur klinischen Besserung) ist im Gegensatz zu Aciclovir sehr effektiv und sehr gut ver-träglich (auch beim Einsatz über einen längeren Zeitraum). Mit dieser Dosierung können bei oraler Gabe auch hohe Konzentrationen am Auge erreicht werden, sodass keine zusätzliche lokale antivirale Behandlung am Auge mehr nötig ist [63]. Famciclovir ist ein in Deutschland in der Humanmedizin zugelassener Wirkstoff, der für die Anwendung bei der Katze umgewidmet werden kann.…”

Tear fluid collection in dogs and cats using ophthalmic sponges

“…lubrication, nutrition, and defense against infection), tears can provide critical data for the clinician and scientist. Among many other applications, tear fluid can be examined for drug pharmacokinetics discovery of biomarkers in ocular diseases (e.g. dry eye disease) and systemic diseases (e.g.…”

“…Microcapillary glass tubes and Schirmer strips, the two most popular tear collection methods in humans, have also been described in animals, but present several drawbacks. Microcapillary tubes require several minutes of collection to obtain small tear volumes and can result in trauma, especially in uncooperative veterinary patients.…”