Famciclovir (FAMVIR®)

Famciclovir is an antiviral with efficacy and safety comparable to aciclovir, but famciclovir's more favorable pharmacokinetic profile enables a less frequent dosing regimen. Future trials will likely determine famciclovir's role in the suppression of HBV.

currently approved dosing regimen of famciclovir for the treatment of herpes zoster (shingles) is 500 mg rid for 7 days; for recurrent genital herpes it is 125 mg bid for 5 days. This treatment is also effective for treatment of first episode genital herpes at a dose of 250 mg rid for 5 days and chronic suppression of recurrences at a dose of 250 mg bid.
However, the last two indications are still pending approval by U.S. regulatory authorities.

STRUCTURE AND DERIVATION
Famciclovir (2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate) is the diacetyl ester of 6-deoxy penciclovir (a synthetic acyclic guanine derivative). Whereas penciclovir itself is very poorly absorbed orally, it was found in animal studies that its dipropionyl and diacetyl 6-deoxy derivatives (BRL 43599 and famciclovir, respectively) gave much improved blood levels of penciclovir. Furthermore, famciclovir was found to be much more stable than B RL 43599.1 Human studies con-firmed that, after oral dosing with famciclovir, more than half the dose is absorbed.

MECHANISM OF ACTION
Penciclovir freely enters both virus-infected and uninfected cells. However, antiherpesviral selectivity relies on rapid phosphorylation to the active form, penciclovir triphosphate, in virus-infected cells only. Viral thymidine kinase (TK) is responsible for the critical rate-limiting initial phosphorylation to penciclovir monophosphate. Metabolism to the diphosphate and active triphosphate forms occur via other cellular enzymes, z Penciclovir triphosphate accumulates to high concentrations in virus-infected cells and interacts with viral DNA polymerase to inhibit viral DNA synthesis. 3 Although penciclovir is phosphorylated in uninfected cells as well, conversion to penciclovir monophosphate is much more readily achieved by viral than by human TK. Thus, concentrations of penciclovir triphosphate remain low in uninfected cells and have minimal effect on human DNA. z PHARMACOKINETICS After oral administration, famciclovir undergoes rapid and extensive absorption in the upper intestine and is rapidly metabolized in the intestinal wall and liver to the active compound penciclo-vir. 4,s Little or no famciclovir is detected in plasma or urine. Inactive metabolites formed include 6deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir. 6 Unlike aciclovir, which has a 10-20% bioavailability, 7 the bioavailability of penciclovir after oral administration of famciclovir is about 77%. 4,8,9 Compared to aciclovir, penciclovir is preferentially taken up and phosphorylated by HSVand VZV-infected cells. Furthermore, penciclovir triphosphate has a very prolonged intracellular half-life in infected cells (7 to 20 hours versus 0.7 to hour for aciclovir triphosphate), z Penciclovir is not metabolized but is eliminated unchanged in the urine. 1 The pharmacokinetics of penciclovir remain largely unaltered in the elderly, making it unnecessary to adjust the dosage in these patients. TM In a study of patients with renal impairment, urinary excretion of pcnciclovir decreased in proportion to the decrease in estimated creatine clearance leading to a recommendation that the dosage interval of famciclovir should be prolonged from 8 hours to 12 hours for patients with moderate renal impairment, and to 24 hours for patients with severe renal impairment. 13 There is no evidence for the need to alter dosage levels of famciclovir in those with well-compensated hepatic impairmerit. 4 The pharmacokinetics of famciclovir have not been studied in patients with severe uncompensated hepatic impairment.
In three studies that investigated the effects of food on the pharmacokinetics and bioavailability of famciclovir,S-17 no clinically significant differences were observed in healthy male volunteers who received famciclovir (250 and 500 mg single doses) 30 minutes after food compared to those who received famciclovir 2 hours before food. When famciclovir 250 mg was administered 30 minutes after food, Cma was reduced by only 20%.

SIDE EFFECTS AND INTERACTIONS
Tolerability data from trials of famciclovir for the treatment of genital herpes and herpes zoster indicate that famciclovir is well tolerated with an adverse event profile similar to placebo. e'ls In an analysis of several trials, side effects did not correlate with increasing daily dose over a range of 125 rag/day to 2,250 rag/day. The most frequent adverse events reported in this analysis were headache, nausea, and diarrhea, which occurred in >2% 4 INFECTIOUS DISEASES 1N OBSTETRICS AND GYNECOLOGY SACKS of patients in both famciclovir and placebo groups. Serious adverse events were no more frequent than placebo and none were classified as related to or probably related to famciclovir. 7 In a recent dose-finding trial of twice-daily oral famciclovir for recurrent genital herpes, 19 there were no significant differences in adverse events or withdrawals between the famciclovir (125,250, and

SPECTRUM OF ANTIVIRAL ACTIVITY
Famciclovir is effective against HSV-1, HSV-2, VCV, and the Epstein-Barr virus (EBV). Penciclovir has also been shown to inhibit viral replication in vitro in duck hepatocytes infected with duck hepatitis B virus (HBV) z,za and famciclovir has been shown to inhibit HBV replication in vivo in hepatic and nonhepatic tissue of ducklings that had been infected in ovo with duck HBV. zz CLINICAL APPLICATIONS Famciclovir is currently licensed to treat VZV herpes zoster (shingles) and HSV genital herpes infections.
Two large clinical trials evaluated famciclovir's effect on rash healing of acute herpes zoster and control of acute pain. A prospective, randomized, placebo-controlled, double-blind trial evaluated famciclovir (500 or 750 mg three times daily for 7 days) in 419 intent-to-treat immunocompetent patients with herpes zoster rash. z3 Famciclovir accelerated the healing of skin lesions (reduced times to full crusting and loss of vesicles, ulcers, and crusts) compared to those given placebo and significantly reduced duration of viral shedding and pain. More importantly, patients receiving famciclovir lost post-herpetic neuralgia (PHN; defined as pain per-sisting after lesion healing) a median of approximately 60 days sooner than those on placebo.
A double-blind, double-dummy, randomized study compared the safety and efficacy of famciclovir (250, 500, or 750 mg three times a day) and aciclovir (800 mg five times a day) for 7 days in 545 immunocompetent patients with acute herpes zoster. z4 For the intent-to-treat population, all doses of famciclovir were equally effective as aciclovir for healing lesions and shortening the time to loss of acute pain. With early treatment, there was approximately 1.5-1.8-fold acceleration in loss of pain over aciclovir, reinforcing the potential benefit of early treatment.
To determine the efficacy and safety of famciclovir in the episodic treatment of recurrent genital herpes, a multicenter, randomized, double-blind, dose-ranging, patient-initiated study was conducted comparing three twice-daily doses (125, 250, and 500 mg) of oral famciclovir with placebo over a 5-day period. 18 Famciclovir at all doses was significantly more effective than placebo at 'reducing time to healing, time to cessation of viral shedding, as well as durations of lesion edema, vesicles, ulcer, and crusts. Times to cessation of all symptoms and of moderate to severe lesion tenderness, pain, and burning were also reduced. Patients who initiated famciclovir prior to viral shedding more frequently aborted the onset of viral shedding. All doses were equally effective and well tolerated.
A similar multicentre, clinic-initiated trial using oral famciclovir at the same three doses again demonstrated reductions of viral shedding, lesion discomfort, lesion duration, and new lesion formation in famciclovir-treated (all doses) patients, zs Lesion tenderness, itching, edema, and ulcer duration were also significantly reduced, and culture positive new lesions were more frequently avoided.
Recent trials have also shown favourable results with famciclovir for both the treatment of first episode genital herpes and for the suppression of recurrent genital herpes, z6 although these are not currently licensed indications in North America. Optimal dosing of famciclovir for first episodes was 250 mg tid, while for suppression, optimal dosing was 250 mg bid, and while for suppression, optimal dosing was 250 mg bid. z7 In a double-blind, placebo-controlled pilot study of 17 patients with chronic HBV infection, famciclovir (250 mg or 500 mg three times daily)