Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment

Boike, Steven C.; Pue, M. A.; Freed, Martin I.; Audet, Patricia R.; Fairless, Amanda J.; Ilson, Bernard E.; Zariffa, Névine; Jorkasky, Diane K.

doi:10.1038/clpt.1994.51

Cited by 57 publications

(24 citation statements)

References 3 publications

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“…The pharmacokinetics of penciclovir and famciclovir have been investigated by standard methods in humans by Boike et al (1994), Fowles et al (1992), Pue & Benet (1993) and in rats by Vere Hodge et al (1989). The pharmacokinetic parameters estimated from the present microdialysis study are consistent with published data (half-life in blood and muscle, AUC and C max after p.o.…”

Section: Discussionsupporting

confidence: 79%

Penciclovir Pharmacokinetics and Distribution to the Brain and Muscle of Rats, Studied by Microdialysis

Borg

Ståhle

1997

Antivir Chem Chemother

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SummaryFamciclovir, the oral form of penciclovir, is a potent, highly selective anti herpesvirus agent licenced for the treatment of herpes zoster (shingles). Some herpesviruses are prone to infect the central nervous system. To obtain guidance for the possible treatment of herpes encephalitis it is important to study the extent of transport of antiviral agents into the brain. We have used microdialysis to sample the unbound extracellular concentration of penciclovir in the gastrocnemic muscle (which corresponds directly to plasma free concentrations) and in the brain of rats under halothane anaesthesia. Penciclovir (50 mg kg-1 ) was given intravenously (i.v.) and samples were taken for 5 h after administration. The AUC (area under the time versus concentration curve) (0-5 h) of penciclovir in the brain was 0.096±0.018 (mean±SEM) of the Aue in muscle while the mean ratio of brain to muscle concentration 5 h post-injection was 0.180±0.084. Famciclovir given per as to rat at a dose of 120 mg kg-1 resulted in a concentration ratio for penciclovir between brain and muscle of 0.415±0.078 at 5 h after administration, while the Aue ratio (0-5 h) was 0.143±0.012. Both of these are higher than after i.v. injection of penciclovir. Penciclovir and famciclovir were also administrated by i.v. infusion (60 and 80 mg kg-1 h-1 respectively). Famciclovir administration (AUe 0.075±0.025 mmol h L-l) did not increase penciclovir transport to the brain compared with penciclovir administration (AUe 0.163±0.018 mmol h L-l).

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Section: Discussionsupporting

confidence: 79%

Penciclovir Pharmacokinetics and Distribution to the Brain and Muscle of Rats, Studied by Microdialysis

Borg

Ståhle

1997

Antivir Chem Chemother

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“…The K m values associated with acyclovir, ganciclovir, and penciclovir transport by OAT2 were 94, 264, and 284 M, respectively. After a single oral therapeutic dose of the prodrugs valacyclovir, valganciclovir, and famciclovir to humans, the maximum plasma concentrations of the active drugs were 29.5 M (acyclovir), 11.7 M (ganciclovir), and 11.2 M (penciclovir) (Boike et al, 1994;Soul-Lawton et al, 1995;Jung and Dorr, 1999). These concentrations are well below the K m values for their interaction with OAT2, and, thus, the transporter would not be saturated by therapeutic levels of the antivirals.…”

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confidence: 99%

Expression of Organic Anion Transporter 2 in the Human Kidney and Its Potential Role in the Tubular Secretion of Guanine-Containing Antiviral Drugs

Cheng¹,

Vapurcuyan²,

Shahidullah³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The organic anion transporters 1 and 3 (OAT1 and OAT3) and organic cation transporter 2 (OCT2) are important for renal tubular drug secretion. In contrast, evidence for OAT2 expression in the human kidney is limited, and its role in renal drug transport is unknown. Both mRNA (real-time polymerase chain reaction) and protein (Western blotting) for OAT2 were detected in renal cortex from eight donors, and interindividual variability in protein levels was 3-fold. OAT2 protein in the renal cortex was localized (by immunohistochemistry) to the basolateral domain of tubules, as were OAT1 and OAT3. The absolute abundance of OAT2 mRNA was similar to that of OAT1 mRNA and 3-fold higher than that of OCT2 mRNA but 10-fold lower than that of OAT3 mRNA. A previous observation that OAT2 transports cGMP led us to examine whether acyclovir, ganciclovir, and penciclovir are OAT2 substrates; they are guanine-containing antivirals that undergo active tubular secretion. Transport of the antivirals into human embryonic kidney cells was stimulated 10-to 20-fold by expression of OAT2, but there was little to no transport of the antivirals by OAT1, OAT3, or OCT2. The K m values for acyclovir, ganciclovir, and penciclovir transport were 94, 264, and 277 M, respectively, and transport efficiencies were relatively high (6-24 l ⅐ min ؊1 ⅐ mg protein ؊1 ).This study provides definitive evidence for the expression of OAT2 in the human kidney and is the first to demonstrate that OAT2, compared with OAT1, OAT3, or OCT2, has a preference for antiviral drugs mainly eliminated in the urine via active secretion.

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“…Additional studies should be conducted with cats of varying breed, sex, and age and should include cats with liver or kidney dysfunction in particular. In human patients administered famciclovir, the rate of penciclovir clearance from plasma is reduced in patients with advanced age or kidney dysfunction, 25,31 and patients with liver disease have reduced BRL42359 metabolism. 25 Consequently, a decrease in famciclovir dosing frequency is recommended for humans with kidney dysfunction, 31 and the same may be necessary for cats with kidney disease.…”

Section: Discussionmentioning

confidence: 99%

“…In human patients administered famciclovir, the rate of penciclovir clearance from plasma is reduced in patients with advanced age or kidney dysfunction, 25,31 and patients with liver disease have reduced BRL42359 metabolism. 25 Consequently, a decrease in famciclovir dosing frequency is recommended for humans with kidney dysfunction, 31 and the same may be necessary for cats with kidney disease. Even though famciclovir dosage is typically not altered in humans with liver dysfunction, it may need to be altered in cats with liver disease because cats inherently have limited hepatic aldehyde oxidase activity (an enzyme required for BRL42359 metabolism), and the activity of that enzyme may be further compromised in cats with liver disease.…”

Section: Discussionmentioning

confidence: 99%

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

Sebbag

Thomasy

Woodward

et al. 2016

ajvr

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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)

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Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment

Cited by 57 publications

References 3 publications

Penciclovir Pharmacokinetics and Distribution to the Brain and Muscle of Rats, Studied by Microdialysis

Penciclovir Pharmacokinetics and Distribution to the Brain and Muscle of Rats, Studied by Microdialysis

Expression of Organic Anion Transporter 2 in the Human Kidney and Its Potential Role in the Tubular Secretion of Guanine-Containing Antiviral Drugs

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

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