Chemical formula: C₁₄H₁₉N₅O₄ Molecular mass: 321.332 g/mol PubChem compound: 3324
Famciclovir is the oral prodrug of penciclovir. Famciclovir is rapidly converted in vivo into penciclovir, which has in vitro activity against herpes simplex viruses (HSV types 1 and 2), varicella zoster virus (VZV), Epstein-Barr virus and cytomegalovirus.
The antiviral effect of orally administered famciclovir has been demonstrated in several animal models: this effect is due to in vivo conversion to penciclovir. In virus-infected cells the viral thymidine kinase (TK) phosphorylates penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by cellular kinases. This triphosphate inhibits viral DNA chain elongation by competitive inhibition with deoxyguanosine triphosphate for incorporation into the growing viral DNA, thus halting virus replication of viral DNA. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. In uninfected cells treated with penciclovir, concentrations of penciclovir-triphosphate are only barely detectable. Hence the probability of toxicity to mammalian host cells is low and uninfected cells are unlikely to be affected by therapeutic concentrations of penciclovir.
Like aciclovir, penciclovir resistance is associated with mutations principally in the thymidine kinase (TK) gene resulting in deficiency or altered substrate specificity of this enzyme, and to a much lesser extent in the DNA polymerase gene. Most aciclovir-resistant HSV and VZV clinical isolates are also resistant to penciclovir, but cross-resistance is not universal.
Results from 11 worldwide clinical studies involving penciclovir (topical or intravenous formulations) or famciclovir in immunocompetent or immunocompromised patients, including studies of up to 12 months treatment with famciclovir, have shown a small overall frequency of penciclovir resistant isolates: 0.2% (2/913) in immunocompetent patients and 2.1% (6/288) in immunocompromised patients. The resistant isolates were mostly found at the start of treatment or in a placebo group, with resistance occurring on or after treatment with famciclovir or penciclovir only in two immunocompromised patients.
Famciclovir is the oral prodrug of the antivirally active compound penciclovir. Following oral administration, famciclovir is rapidly and extensively absorbed and converted to penciclovir. Bioavailability of penciclovir after oral administration of famciclovir was 77%. Mean peak plasma concentration of penciclovir, following a 125 mg, 250 mg, 500 mg and 750 mg oral dose of famciclovir, was 0.8 microgram/ml, 1.6 micrograms/ml, 3.3 micrograms/ml and 5.1 micrograms/ml, respectively, and occurred at a median time of 45 minutes post-dose.
Plasma concentration-time curves of penciclovir are similar following single and repeat (t.i.d. and b.i.d.) dosing, indicating that there is no accumulation of penciclovir on repeated dosing with famciclovir.
The extent of systemic availability (AUC) of penciclovir from oral famciclovir is unaffected by food.
Penciclovir and its 6-deoxy precursor are poorly (<20%) bound to plasma proteins.
Famciclovir is eliminated principally as penciclovir and its 6-deoxy precursor, which are excreted in urine. No unchanged famciclovir has been detected in urine. Tubular secretion contributes to the renal elimination of penciclovir.
The terminal plasma half-life of penciclovir after both single and repeat dosing with famciclovir was approximately 2 hours.
Evidence from preclinical studies has shown no potential for induction of cytochrome P450 enzymes and inhibition of CYP3A4.
Uncomplicated herpes zoster infection does not significantly alter the pharmacokinetics of penciclovir measured after the oral administration of famciclovir. The terminal plasma half-life of penciclovir in patients with herpes zoster was 2.8 h and 2.7 h, respectively, after single and repeated dosing of famciclovir.
The apparent plasma clearance, renal clearance, and plasma elimination rate constant of penciclovir decreased linearly with reductions in renal function, both after single and repeated dosing. Dose adjustment is necessary in patients with renal impairment.
Mild and moderate hepatic impairment had no effect on the extent of systemic availability of penciclovir following oral administration of famciclovir. No dose adjustment is recommended for patients with mild and moderate hepatic impairment. The pharmacokinetics of penciclovir have not been evaluated in patients with severe hepatic impairment. Conversion of famciclovir to the active metabolite penciclovir may be impaired in these patients resulting in lower penciclovir plasma concentrations, and thus possibly a decrease of efficacy of famciclovir.
Repeated oral dosing of famciclovir (250 or 500 mg three times daily) to paediatric patients (6-11 years) infected with hepatitis B did not have a notable effect on the pharmacokinetics of penciclovir compared to single dose data. There was no accumulation of penciclovir. In children (1-12 years) with herpes simplex virus infection or chickenpox given single oral doses of famciclovir, the apparent clearance of penciclovir increased with body weight in a nonlinear manner. The plasma elimination half-life of penciclovir tended to decrease with decreasing age, from an average of 1.6 hours in the patients aged 6-12 years to 1.2 hours in patients aged 1-<2 years.
Based on cross-study comparisons, the mean penciclovir AUC was about 30% higher and penciclovir renal clearance about 20% lower after oral administration of famciclovir in older volunteers (65-79 years) compared to younger volunteers. Partly this difference may be due to differences in renal function between the two age groups. No dose adjustment based on age is recommended unless renal function is impaired.
Small differences in renal clearance of penciclovir between females and males have been reported and were attributed to gender differences in renal function. No dose adjustment based on gender is recommended.
Studies on safety pharmacology and repeated dose toxicity reveal no special hazard for humans.
Famciclovir was not found to be genotoxic in a comprehensive battery of in vivo and in vitro tests designed to detect gene mutation, chromosomal damage and repairable damage to DNA. Penciclovir, in common with other substances of this class, has been shown to cause mutations/chromosomal aberrations in human lymphocytes and in the L5178Y mouse lymphoma assay at concentrations at least 25-fold to 100-fold, respectively higher than the maximum concentration reached in human plasma after a single oral famciclovir dose of 1500 mg. Penciclovir was negative in the bacterial Ames test and there was no evidence of increased DNA repair in vitro.
Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intravenously at doses highly toxic to bone marrow (≥500 mg/kg corresponding to ≥810 times the maximum human dose based on body surface area conversion).
At high doses in female rats, there was an increased incidence of mammary adenocarcinoma, a tumour commonly observed in the strain of rats used in the carcinogenicity study. There was no effect on the incidence of neoplasia in male rats treated at doses up to 240 mg/kg/day (corresponding to a 38.4 mg/kg human equivalent dose or 1.3-fold of the highest recommended total daily dose of 1500 mg famciclovir or a patient of 50 kg body weight) or in mice of either sex at doses up to 600 mg/kg/day (corresponding to a 48 mg/kg human equivalent dose or 1.6-fold of the highest recommended total daily dose).
Impaired fertility (including histopathological changes in the testis, altered sperm morphology, reduced sperm concentration and motility, and reduced fertility) was observed in male rats after 10 weeks of dosing at 500 mg/kg/day (corresponding to a 80 mg/kg human equivalent dose or 2.7-fold of the highest recommended total daily dose). Furthermore, testicular toxicity was noted in the general toxicity studies. This finding was reversible and has also been observed with other substances of this class. Animal studies did not indicate any negative effect on female fertility at doses up to 1000 mg/kg/day (corresponding to a 160 mg/kg human equivalent dose or 5.3-fold of the highest recommended total daily dose).
Embryofetal development studies showed no evidence of adverse effects at oral doses of famciclovir and intravenous doses of penciclovir corresponding to 0.7- to 5.3- fold of the highest recommended total daily dose of famciclovir.
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