Antiviral Chemistry & Chemotherapy 15:251–253 Pointer Recent clinical experience with famciclovir – a ‘third generation’ nucleoside

Arun Chakrabarty1,3*, Stephen K Tyring2, Karl Beutner1 and Michael Rauser3

1Solano Research, Davis, Calif., USA 2Center for Clinical Studies, Houston, Tex., USA 3Department of Opthamology, Loma Linda University School of Medicine, Loma Linda, Calif., USA

*Correspondence: Tel: +1 530 400 8814; Fax: +1 951 925 9252; E-mail: [email protected]

The herpesviruses continue to produce consider- the orally bioavailable and able morbidity in man. Once infected with herpes famciclovir have been introduced. These com- simplex (HSV), the virus remains dormant within pounds offer high oral bioavailabilty and deliver the nervous system and may reactivate if pro- acyclovir and , respectively, to the tar- voked by stress, trauma and/or other factors. To get cells by means of more convenient dosing date, there is no cure, but antiviral medication can schedules. This short review points to recent expe- reduce duration and severity of symptoms and rience with famciclovir in the management of HSV prophylaxis can suppress recurrent episodes of and varicella-zoster virus. disease. The second-generation nucleo- sides, acyclovir and penciclovir, are effective Keywords: famciclovir, oral , penci- inhibitors with low toxicity; both, however, have clovir, orofacial herpes, genital herpes, herpes relatively low oral bioavailability. Subsequently, zoster, ophthalmic zoster

Introduction

Antiviral chemotherapy is the standard practice in the 1 h after famciclovir administration in a fasting condition and management of alpha-herpesvirus infections; this article 2 h in a non-fasting state (Gill et al., 1996). The parent will focus on famciclovir (famvir). Famciclovir was among compound was not recovered from plasma or urine samples the first antivirals to have been developed with a view to (Gill et al., 1996). It is the oral form of penciclovir, a nucleoside achieving better oral bioavailability and/or intracellular analogue, which has a similar antiviral spectrum to acyclovir for . The pharmacokinetic profile of famci- the herpesviruses with approximately similar potency, although clovir makes it an excellent, efficacious and well-tolerated penciclovir generates higher intracellular triphosphate concen- alternative to the more traditionally prescribed acyclovir. trations. In tissue culture experiments, penciclovir triphosphate was reported to have a prolonged intracellular half-life; 10–20 h Mechanism and pharmacokinetics in virus (HSV)-1- and HSV-2-infected cells compared with 0.7–1 h in HSV-1- and HSV-2-infected cells The chemical name of famciclovir is diacetyl-6-deoxy-9-(4- for acyclovir (Crumpacker et al., 1996). Similar to acyclovir, hydroxy-3-hydroxymethyl-but-1-yl). Famciclovir is penciclovir requires initial activation by viral-encoded thymi- an acyclic guanosine analogue (Table 1) and has no dine kinase followed by cellular kinases, in order to inhibit viral antiviral activity itself until it is metabolized into penci- DNA polymerase. This occurs via competition between clovir. The drug is converted to penciclovir in the liver, via deoxyguanosine triphosphate and penciclovir triphosphate, deacetylation and oxidation, and is primarily excreted by which competitively inhibits viral DNA polymerase and is the kidneys, mainly as penciclovir. Plasma concentrations incorporated into the extending DNA chain preventing further of penciclovir increase linearly with the therapeutic dose elongation. The enhanced oral bioavailability of famciclovir range of famciclovir (Pue et al., 1994). The peak plasma provides a simpler dosing schedule as compared with penci- concentration of penciclovir reached a maximum within clovir. In addition, famciclovir and penciclovir are not

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Table 1. Famciclovir Table 2. Clinical indications for famciclovir

Company name Orofacial herpes Episodic therapy: Compound Famciclovir (famvir) (HSV-1) 500 or 250 mg po three-times daily Structure for 5 days N N Prophylaxis after laser resurfacing: 500 or 250 mg po twice daily N H2N N Genital herpes Initial therapy: O (HSV-2 or HSV-1) 250 mg po three-times daily for 10 days Episodic therapy: H N O 3 125 mg po twice daily for 5 days Suppressive therapy: 250 mg po twice daily for up to 1 year H3N O HSV infections in HIV positive patients: O 500 mg po twice daily for 8 weeks or longer Description Oral prodrug of penciclovir Herpes zoster/ Immunocompetent: post-herpetic 500 or 750 mg po three-times daily for Antiviral spectrum HSV-1 neuralgia (VZV) 7 days HSV-2 Immunocompromised: VZV 500 mg po three-times daily for 10 days Ophthalmic 500 mg po three-times daily for 7 days VZV, varicella-zoster virus. zoster (VZV)

po, per orally. metabolized through the cytochrome P450 system, thereby enabling dosing administration in patients with multiple co- morbidities and concomitant medications. Famciclovir is more frequently employed in the manage- ment of primary and episodic genital herpes along with Clinical indications long-term suppression. Famciclovir is effective at 250 mg three-times daily for 10 days for primary genital herpes and Tyring and Beutner et al. (2000) conducted a comparison 125 mg twice daily for 5 days for recurrent genital herpes trial of famciclovir versus valacyclovir that did not illustrate outbreaks (Lin et al., 2003). In a large placebo-controlled any significant differences for either . trial, famciclovir was shown to be effective for episodic Famciclovir is mainly effective against HSV-1, HSV-2 and therapy for recurrent genital herpes (Sacks et al., 1996). A varicella-zoster virus (VZV). The predominant clinical separate comparison trial with acyclovir revealed twice-daily indications are orofacial herpes, genital herpes and herpes famciclovir to be as effective and tolerable as five-times daily zoster (see Table 2). Its main competitor for these clinical acyclovir for recurrent genital herpes (Chosidow et al., 2001). indications is valacylovir, the oral prodrug of acyclovir. The Suppressive therapy is encouraged when recurrences are choice between the two drugs is likely to depend on the severe, frequent and/or emotionally disturbing. For patients availability, tolerance, physician awareness, compliance and experiencing recurrent outbreaks (that is, more than six per cost issues rather than on efficacy and pharmokinetic para- year), famciclovir suppressive dosing at 250 mg twice daily meters. These antivirals have limitations since neither for 4 consecutive months was demonstrated to be a safe and provides a cure for herpesvirus infections but merely alters effective regimen for the suppression of recurrent genital the clinical course of disease. herpes (Mertz et al., 1997). There was a reduction in Famciclovir is used to treat orolabial herpes either as frequency of outbreaks as well as an increase in length of episodic or prophylactic therapy. A double-blind, random- time until the next successive episode. Antiviral therapy with ized, dose-ranging study demonstrated the benefit of famci- famciclovir at 500 mg twice daily for 8 weeks resulted in clovir 500 or 250 mg three-times daily for 5 days as early significant reductions in symptoms of HSV infection among episodic intervention for UV-induced orofacial herpes recur- HIV-positive patients (Schacker et al., 1998). Genital herpes rences (Spruance et al., 1999). A slight advantage of the is most often transmitted while the patient is asymptomatic higher dose was noted. Famciclovir 250 or 500 mg twice during periods of viral shedding. Suppressive treatment with daily revealed an effective prophylactic strategy subsequent famciclovir has also demonstrated a reduction in asympto- to cutaneous surface laser resurfacing for herpes orofacial matic viral shedding (Sacks, 2004). Further trials to docu- recurrence (Wall et al., 1999). The higher dose is encouraged ment the effects of genital herpes transmission with for patients with a prominent history of orofacial herpes. long-term famciclovir suppression are needed.

252 ©2004 International Medical Press Recent clinical experience with famciclovir

Post-herpetic neuralgia remains a principal cause of herpes infections: a parallel-groups, randomized, double-blind clin- ical trial. British Journal of Dermatology 144:818–824. post-infectious morbidity subsequent to a herpes zoster eruption. Tyring et al. demonstrated considerable safety and Crumpacker C (1996) The pharmacological profile of famciclovir. Seminars in Dermatology 15:14–26. efficacy of famciclovir (500 mg or 750 mg three-times daily Gill KS & Wood MJ (1996) The clinical pharmacokinetics of famci- for 7 days) in a multicentre, double-blind, placebo- clovir. Clinical Pharmacokinetics 31:1–8. controlled trial (Tyring ., 1995). Famciclovir recipients et al Lin P, Torres G & Tyring SK (2003) Changing paradigms in derma- had accelerated lesion healing and a more rapid resolution tology: antivirals in dermatology. Clinics in Dermatology 21:426–446. of post-herpetic neuralgia in patients more than 50 years Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler SL, Goade D old in comparison with placebo recipients. Tyring and & Tyring SK (1997) Oral famciclovir for suppression of recurrent Beutner et al. conducted a comparison trial of famciclovir genital herpes simplex virus infection in women. A multicenter, dou- ble-blind, placebo-controlled trial. Collaborative Famciclovir Genital versus valacyclovir that did not illustrate any significant Herpes Research Group. Archives of Internal Medicine 157:343–349. differences for either antiviral drug in terms of resolution of Pue MA, Pratt SK, Fairless AJ, Fowles S, Laroche J, Georgiou P & post-herpetic neuralgia pain (Tyring et al., 2000). For Prince W (1994) Linear pharmacokinetics of penciclovir following immunocompromised patients with herpes zoster, famci- administration of single oral doses of famciclovir 125, 250, 500 and 750 mg to healthy volunteers. Journal of Antimicrobial Chemotherapy clovir at 500 mg three-times daily for 10 days has also 33:119–127. shown adequate safety and efficacy (Tyring et al., 2001a). Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J & Shafran SD (1996) Famciclovir’s documented efficacy in the management Patient-initiated, twice-daily oral famciclovir for early recurrent of uncomplicated herpes zoster in immunocompetent and genital herpes. A randomized, double-blind multicenter trial. immunocompromised patients initiated the role of famci- Canadian Famciclovir Study Group. Journal of American Medical Association 76:44–49. clovir therapy for ophthalmic zoster patients. In a separate Sacks SL (2004) Famciclovir suppression of asymptomatic and trial, Tyring et al. demonstrated similar safety and efficacy symptomatic recurrent anogenital herpes simplex virus shedding in for famciclovir 500 mg three-times daily versus acyclovir women: a randomized, double-blind, double-dummy, placebo- 800 mg five-times daily for ophthalmic herpes zoster, with controlled, parallel-group, single-center trial. Journal of Infectious a more convenient dosage schedule offered by famciclovir Diseases 189:1341–1347. therapy (Tyring et al., 2001b). Famciclovir has established Schacker T, Hu HL, Koelle DM, Zeh J, Saltzman R, Boon R, Shaughnessy M, Barnum G & Corey L (1998) Famciclovir for the itself as a safe, efficacious and well-tolerated antiviral in the suppression of symptomatic and asymptomatic herpes simplex therapeutic arsenal against herpes zoster. virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial. Annals of Internal Medicine 128:21–28. Conclusion Spruance SL, Rowe NH, Raborn GW, Thibodeau EA, D’Ambrosio JA & Bernstein DI (1999) Peroral famciclovir in the treatment of experimental ultraviolet radiation-induced herpes simplex labialis: The role of famciclovir in the management of viral infections a double-blind, dose-ranging, placebo-controlled, multicenter trial. is currently expanding. Preliminary evidence suggested that Journal of Infectious Diseases 179:303–310. famciclovir may have a role as adjunct therapy in the Tyring S, Barbarash RA, Nahlik JE, Cunningham A, Marley J, Heng management of although its use for this indica- M, Jones T, Rea T, Boon R & Saltzman R (1995) Famciclovir for the treatment of acute herpes zoster: effects on acute disease and tion is not currently being progressed. Theoretically, : a randomized, double-blind, placebo- however, the addition of famciclovir to the current antivirals controlled trial. Annals of Internal Medicine 123:89–96. of hepatitis B may reduce the risk of resistance development. Tyring SK, Beutner KR, Tucker BA, Anderson WC & Crooks RJ Further trials of famciclovir in combination with , (2000) Antiviral therapy or herpes zoster: randomized, controlled of valacyclovir and famciclovir therapy in immunocom- or as monotherapy for lamvudine-resistant hepatitis B infec- petent patients 50 years and older. Archives of Family Medicine tions, are warranted. Famciclovir provides a safe, efficacious 9:863–869. and well-tolerated antiviral regimen. Its unique pharmacoki- Tyring S, Belanger R, Bezwoda W, Ljungman P, Boon R, Saltzman netic profile enables a convenient and patient-friendly RL (2001a) A randomized, double-blind trial of famciclovir versus method of administration. Favourable administration acyclovir for the treatment of localized dermatomal herpes zoster in immunocompromised patients. Cancer Investigation 19:13–22. enhances patient compliance, which leads to better outcomes Tyring S, Engst R, Corriveau C, Robillard N, Trottier S, Van in the management of viral infections. Slycken S, Crann RA, Locke LA, Saltzman R & Palestine AG; Collaborative Famciclovir Ophthalmic Zoster Research Group References (2001b) Famciclovir for ophthalmic zoster: a randomised controlled study. British Journal of Ophthalmology 85:576–581. Chosidow O, Drouault Y, Leconte-Veyriac F, Aymard M, Ortonne Wall SH, Ramey SJ & Wall F (1999) Famciclovir as as antiviral pro- JP, Pouget F, Revuz J, Decazes JM & Malkin JE (2001) Famciclovir phylaxis in laser resurfacing procedures. Plastic & Reconstructive vs. aciclovir in immunocompetent patients with recurrent genital Surgery 104:1103–1108.

Received 13 July 2004; accepted 27 July 2004

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