Pharmacokinetics of Famciclovir in Subjects with Chronic Hepatic Disease

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

doi:10.1002/j.1552-4604.1994.tb04732.x

Cited by 31 publications

(9 citation statements)

References 24 publications

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“…Indeed, the pharmacokinetic of famciclovir has been studied in subjects with various chronic liver diseases. 38 The results showed a decreased C max and an increased T max whereas the area under the curve of penciclovir was not modified, suggesting a decrease in the rate, but not in the extent, of systemic availability of penciclovir in patients with liver disease compared to healthy subjects. 38 A careful pharmacokinetic study in patients with HBV related liver cirrhosis is currently ongoing and its results are awaited to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 84%

Transient selection of a hepatitis B virus polymerase gene mutant associated with a decreased replication capacity and famciclovir resistance

et al. 1999

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Prolonged therapy for chronic hepatitis B (HBV) with nucleoside analogs may result in the emergence of HBV mutants resistant to antivirals. Here, we describe the transient selection of an HBV polymerase gene mutant that was associated with viral persistence in an immune competent patient treated with famciclovir. Viral polymerase gene sequence was analyzed directly on polymerase chain reaction (PCR) products and also after cloning. The results showed the transient selection of a V542I mutant in the C domain of the viral polymerase. This mutation was associated with a stop codon at amino acid position 199 in the overlapping S gene. The mutated sequence was subcloned in a vector expressing the entire HBV pregenome to study its replication capacity after transient transfection in cultured hepatoma cells. The results showed that the V542I mutant has a decreased replication capacity compared with wild type virus and does not produce HBsAg. The sensitivity of the V542I mutant to penciclovir, the active metabolite of famciclovir, was further studied in tissue culture. This mutant was shown to be resistant to penciclovir, but remained sensitive to lamivudine, as was subsequently observed in vivo. Recently, the antiviral efficacy of new nucleoside analogs, famciclovir and lamivudine, has been assessed in chronically hepatitis B virus (HBV)-infected patients. 1,2 Famciclovir is the oral prodrug of penciclovir (9-[4-hydroxy-3 hydroxymethylbut-1-yl] guanine; BRL 39123)-triphosphate, which was shown to inhibit hepadnavirus replication in vitro in tissue culture and in vivo in animal models of HBV infection. 3,4 It was further shown that penciclovir triphosphate not only inhibits the DNA dependent DNA polymerase activity of the HBV polymerase, 5 but also the RNA-dependent activity of this enzyme, i.e., reverse transcription, by inhibiting the synthesis of the short DNA primer for reverse transcription. 6 Preliminary evidence suggested that famciclovir may have clinical utility in the treatment of chronic hepatitis B patients 7 and in orthotopic liver transplant patients. 8 A first placebocontrolled pilot study showed a fall of HBV DNA levels by more than 90% in 6 out of 11 evaluable patients. 7 Kruger et al. have reported, in 11 patients with HBV recurrence after orthotopic liver transplantation, that famciclovir treatment could induce a significant decrease of serum viral DNA levels in 90% of the patients and a clearance of HBV DNA detected by PCR in 36%, without significant side effect. 8 A large multicenter placebo controlled trial including 333 patients showed the clinical efficacy of a 16-week course of famciclovir with a dose-dependent antiviral effect accompanied by a decrease of serum ALT levels and a significant increase of anti-HBe antibody seroconversion compared with the placebo group. 9 By using the results of clinical trials for the evaluation of another promising nucleoside analog, lamivudine (3TC or [(Ϫ)-␤-L-2Ј, 3Ј-Dideoxy-3Јthiacytidine]), Nowak et al. have determined the kinetics of viral clearance during an...

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Section: Discussionmentioning

confidence: 84%

Transient selection of a hepatitis B virus polymerase gene mutant associated with a decreased replication capacity and famciclovir resistance

et al. 1999

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“…Since penciclovir is primarily excreted via the kidneys, dose adjustment for renal insufficiency is recommended for famciclovir. 10 Its dose may also vary based on indications.…”

Section: Discussionmentioning

confidence: 99%

Famciclovir substitution for patients with acyclovir-associated renal toxicity

Htwe

Bergman

Koirala

2008

Journal of Infection

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“…13 There is no evidence for the need to alter dosage levels of famciclovir in those with well-compensated hepatic impairment. 14 The pharmacokinetics of famciclovir have not been studied in patients with severe uncompensated hepatic impairment.…”

Section: Pharmacokineticsmentioning

confidence: 99%