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Valaciclovir, the L-valyl ester of aciclovir (acyclovir), is an oral prodrug that undergoes rapid and extensive first-pass metabolism to yield aciclovir and the essential amino acid L-valine. Aciclovir, the active antiviral component of valaciclovir, shows good in vitro activity against the herpesviruses herpes simplex virus (HSV)-1, HSV-2 and varicella zoster virus.
The bio availability of aciclovir from oral valaciclovir is considerably greater than that achieved after oral aciclovir administration. Thus, valaciclovir delivers therapeutic aciclovir concentrations when administered in a less frequent oral dosage regimen than is required for aciclovir.
Valaciclovir is an effective treatment for herpes zoster in immunocompetent adults. In a large comparative study that included patients ≥50 years of age, valaciclovir (1000mg 3 times daily for 7 or 14 days) and oral aciclovir (800mg 5 times daily) were equally effective in achieving resolution of cutaneous zoster lesions. Importantly, valaciclovir was significantly more effective than aciclovir in reducing the duration of zoster-associated pain.
Preliminary results of several studies indicate that valaciclovir (500 to 1000mg twice daily for 5 to 10 days) is as effective as aciclovir (200mg 5 times a day for 5 to 10 days) in the treatment of genital herpes. In patients with first or recurrent episodes of genital herpes, valaciclovir reduced the duration of viral shedding, hastened lesion healing and decreased lesion-associated pain. Valaciclovir was also effective in suppressing recurrent episodes of genital herpes and significantly prolonged the time to a recurrent episode of infection compared with placebo.
Valaciclovir is a well tolerated drug; in herpes zoster and HSV studies its tolerability profile was similar to that of aciclovir or placebo.
Valaciclovir represents an advance in antiherpes drug therapy and is a useful treatment option for patients with herpes zoster or genital herpes. It is at least as effective as aciclovir and is administered in a more convenient oral dosage regimen. Thus, valaciclovir may ultimately succeed aciclovir as a first-line treatment for genital herpes or herpes zoster.
After oral administration and absorption, valaciclovir is converted to aciclovir (acyclovir), which is the active antiviral component of valaciclovir. Thus, the antiviral activity of valaciclovir is the same as that of aciclovir.
Aciclovir is preferentially converted to its active antiviral form, aciclovir tri-phosphate, by herpesvirus-encoded enzymes (to the monophosphate) and cellular enzymes (from the monophosphate to the triphosphate) in herpesvirus-infected cells. Aciclovir triphosphate subsequently inhibits herpesvirus DNA polymerase, terminates viral DNA chain elongation and therefore completely prevents replication of viral DNA.
Aciclovir has good inhibitory activity against HSV (herpes simplex virus) and VZV (varicella zoster virus) in vitro. The descending order of susceptibility to the drug is HSV-1, HSV-2 and VZV Aciclovir is also active against Epstein-Barr virus and has moderate activity against cytomegalovirus and human herpesvirus 6. The antiviral activity of aciclovir has also been demonstrated in animal models of ocular, cutaneous and genital HSV infection.
Resistance of HSV or VZV to aciclovir is rare and almost all resistant isolates occur as a result of a deficiency in thymidine kinase. Nearly all clinical HSV or VZV isolates with resistance to aciclovir have been obtained from immuno-compromised patients who have received prolonged aciclovir therapy.
In healthy volunteers and patients, valaciclovir is readily absorbed after oral administration and undergoes rapid and extensive first-pass metabolism to yield aciclovir and the essential amino acid L-valine.
The bioavailability of aciclovir following valaciclovir administration is greater than after oral aciclovir administration (54 vs 12 to 20%). The pharmacokinetics of aciclovir after valaciclovir were similar after single- or multiple-dose administration of valaciclovir in healthy adult volunteers. After single 100 to 1000mg doses of valaciclovir, the area under the plasma concentration-time curve (AUC) for aciclovir ranged from 2.28 to 19.5 mg/L • h. Following oral valaciclovir 2000mg 4 times daily, the daily AUC for aciclovir was 109 mg/L • h, which was similar to the daily systemic aciclovir exposure achieved with intravenous aciclovir 10 mg/kg 3 times daily (107 mg/L • h).
The mean plasma elimination half-life (t½) of aciclovir after administration of single oral valaciclovir doses (100 to 1000mg) or oral valaciclovir 1000 to 8000 mg/day for 8 to 11 days to healthy volunteers was 2.62 to 3.13 hours. In patients with end-stage renal disease the t½ of aciclovir after a single 1000mg dose of valaciclovir was prolonged to 14 hours. However, one third of aciclovir may be removed by dialysis in these patients.
Metabolites of aciclovir (from valaciclovir) are well characterised and pharmacologically inactive. The kidneys are the main route of elimination of valaciclovir, aciclovir and other metabolites of the drug. Valaciclovir and aciclovir are also excreted in the faeces. After single or multiple doses (100 to 2000mg) of valaciclovir, aciclovir accounted for 80 to 85% of the recovered drug, 7 to 12% was recovered as metabolites and <1% as valaciclovir.
No clinically significant interactions were observed between valaciclovir and a thiazide diuretic, an aluminium- and magnesium-containing antacid, digoxin, cimetidine, probenecid, or a combination of cimetidine and probenecid.
The therapeutic efficacy of valaciclovir has been investigated in immunocompetent patients with herpes zoster (shingles) or genital HSV. Studies in immuno-compromised patients are in progress. Treatment was initiated within 72 hours of initial signs or symptoms of infection in patients with herpes zoster or first-episode genital herpes. In recurrent genital herpes studies, treatment was patient-initiated and commenced within 24 hours of the appearance of initial symptoms of a recurrence.
Valaciclovir 1000mg 3 times daily, administered for either 7 or 14 days, was as effective as 7 days’ treatment with aciclovir (800mg 5 times a day) in achieving resolution of the zoster rash in a large study that included 1141 patients (aged ≥50 years) with herpes zoster (including patients with ophthalmic zoster). In addition, both regimens of valaciclovir significantly hastened the resolution of zoster-associated pain by, on average, 22 or 34%, compared with aciclovir. Valaciclovir 1000mg 3 times a day for 7 days was also an effective treatment for younger patients (aged 18 to 50 years) with herpes zoster and was significantly more effective than placebo in terminating the formation of new zoster lesions. However, the relative effects of valaciclovir and placebo on other efficacy parameters, including the duration of zoster-associated pain, have not yet been reported.
Accumulating data, some of which are at present available in abstract form only, indicate that valaciclovir is also an effective treatment for patients with first or recurrent episodes of genital HSV. In a single study that included patients with a first episode of genital herpes, there were no differences in efficacy between valaciclovir 1000mg twice daily and aciclovir 200mg 5 times a day as determined by times to lesion healing, resolution of viral shedding and pain resolution. Valaciclovir 500 or 1000mg twice a day and aciclovir 200mg 5 times a day also demonstrated similar efficacy in patients with recurrent episodes of genital herpes and both agents significantly hastened the resolution of episodes (median times to lesion healing 4.0 to 4.8 days) compared with placebo (5.9 days). Recipients of valaciclovir 500 or 1000mg twice daily experienced a higher incidence of aborted recurrent episodes of genital herpes than aciclovir recipients. Valaciclovir (500mg once daily) has also been shown to suppress recurrent episodes of genital herpes. In patients who had experienced ≥8 recurrences of infection during the previous year, valaciclovir was significantly more effective than placebo in prolonging the time between recurrent episodes.
Valaciclovir is, like oral aciclovir, a well tolerated drug. In patients with herpes zoster, the most common adverse events reported during treatment with valaciclovir 1000mg 3 times daily were nausea, vomiting, headache and diarrhoea; the incidence of these events was similar to that in patients with herpes zoster who received oral aciclovir 800mg 5 times a day. Valaciclovir has also shown good tolerability in patients with genital herpes, individuals with hepatic and renal impairment and elderly volunteers. In patients with recurrent genital herpes, the tolerability profile of valaciclovir (500 to 1000mg twice daily) was similar to that of placebo.
Dosage and Administration
For adults with herpes zoster, the recommended dosage of valaciclovir is 1000mg 3 times daily for 7 days. Treatment with the drug should be initiated at the first signs and symptoms of herpes zoster, preferably within 72 hours of the appearance of the zoster rash.
The recommended dosage of valaciclovir for patients with either a first episode or recurrent episodes of genital herpes is 500mg twice daily for 5 days, which may be extended to 10 days if necessary in first episodes of genital herpes, as these may be more severe.
Dosage modification of valaciclovir is not usually required in elderly patients, but the dosage of the drug should be reduced in patients with moderate to severe renal impairment.
KeywordsHerpes Zoster Acyclovir Genital Herpes Famciclovir Valaciclovir
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- 1.Crooks RJ, Murray A. Valaciclovir — a review of a promising new antiherpes agent. Antiviral Chem Chemother 19945 Suppl. 1: 31–7Google Scholar
- 12.Vere Hodge RA, Cheng Y-C. The mode of action of penciclovir. Antiviral Chem Chemother 1993; 4 Suppl. 1: 13–24Google Scholar
- 13.Bacon TH, Schinazi RF. An overview of the further evaluation of penciclovir against herpes simplex virus and varicella zoster virus in cell culture highlighting contrasts with acyclovir. Antiviral Chem Chemother 1993; 4 Suppl. 1: 25–36Google Scholar
- 14.Glaxo Wellcome. Valaciclovir Prescribing Information. US, 1995Google Scholar
- 15.Littler E. Safety and efficacy issues of herpesvirus drugs. Antiviral Chem Chemother 1994; 5 Suppl. 1: 11–6Google Scholar
- 21.Collins P, Nixon Ellis M. Sensitivity monitoring of clinical isolates of herpes simplex virus to acyclovir. J Med Virol 1993 Suppl. 1: 58–66Google Scholar
- 22.Boyd MR, Safrin S, Kern ER. Penciclovir: a review of its spectrum of activity, selectivity and cross-resistance pattern. Antiviral Chem Chemother 1993; 4 Suppl. 1: 3–11Google Scholar
- 27.First MR, Blum MR, Brennan P, et al. Pharmacokinetics (PK) of 256U87, an acyclovir (ACV) prodrug in renal transplant (RTX) patients [abstract]. Clin Pharmacol Ther 1993 Feb; 53: 238Google Scholar
- 28.On NT, Ehninger G, Gluckman E, et al. Acyclovir pharmacokinetics following oral multiple-dose of valaciclovir (Valtrex™) in allogeneic BMT patients [abstract]. Bone Marrow Transplant 1995 Mar; 15 Suppl. 2: S122Google Scholar
- 30.Coakley D, Weiler S, Blum MR, et al. Valtrex(Rm) (valaciclovir) administration achieves increased acyclovir concentrations in multiple populations [abstract]. Pharmacotherapy 1994 May–Jun; 14: 373Google Scholar
- 31.Posner J, Soul-Lawton J, Weiler S, et al. Valtrex (Rm) (valaciclovir) — bioavailability in différent patient populations [abstract]. Can J Infect Dis 1995 Jul; 6 Suppl. C: 287CGoogle Scholar
- 33.Obenshain MK, Warwick JC, Weiler S, et al. The absence of a food effect on acyclovir (ACV) bioavailability from a single Valtrex™ (VACV) dose. Pharm Res 1994; 11 Suppl. 10: S435Google Scholar
- 35.Carrington D. Prospects for improved efficacy with antiviral prodrugs: will valaciclovir and famciclovir meet the clinical challenge? Int Antiviral News 1994 Apr; 2: 50–3Google Scholar
- 37.de Miranda P, Burnette TC, Smith C, et al. Mechanisms of the enhanced oral bioavailability of acyclovir with the prodrug valacyclovir HC1 (Valtrex™) [abstract]. 34th International Conference on Antimicrobial Agents and Chemotherapy. 1994 Oct 4–7; Orlando, 83Google Scholar
- 39.Soul-Lawton J, Chan PQ, Posner J, et al. Lack of interaction between valaciclovir, the L-valyl ester of aciclovir, and digoxin. 7th International Congress for Infectious Diseases. 1996 June 10–13; Hong Kong, 40Google Scholar
- 44.Jeffries D, Barton S, Johnson R, et al. Issues in herpes management. Antiviral Chem Chemother 1994; 5 Suppl. 1: 23–9Google Scholar
- 45.Smiley ML, The International Valaciclovir Zoster Study Group. The efficacy and safety of valaciclovir for the treatment of herpes zoster. 33rd International Conference on Antimicrobial Agents and Chemotherapy. 1993 Oct 17–20; New Orleans, 340Google Scholar
- 46.Johnson RW, Crooks RJ, The International Valaciclovir Zoster Study Group. The clinical efficacy of valaciclovir in the treatment of herpes zoster [abstract]. J Europ Acad Dermatol and Venereol 1994; 5 Suppl. 1: S75.Google Scholar
- 47.Murray AB. Valaciclovir — an improvement over aciclovir for the treatment of zoster. Antiviral Chem Chemother 1995; 6 Suppl. 1: 34–8Google Scholar
- 48.Fife KH, International Valaciclovir HSV Study Group. Valaciclovir or acyclovir for the treatment of first episode genital herpes [abstract]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1995 Sep 17–20; San Francisco, 243Google Scholar
- 49.Patel R, Delehanty J. Valaciclovir for the treatment of first episode genital herpes. 1st European Congress of Antimicrobial Chemotherapy. 1996 May 14–17, GlasgowGoogle Scholar
- 51.International VHSVSG, Smiley ML. Valaciclovir and acyclovir for the treatment of recurrent genital herpes simplex virus infections [abstract]. 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy. 1993 Oct 17–20; New Orleans, 341Google Scholar
- 52.GlaxoWellcome plc. Regulatory Submission report BQRT/ 95/0011Google Scholar
- 53.Kinghorn GI, Fiddian AP, The International Valaciclovir HSV Study Group. Prevention of lesion development in recurrent genital herpes with oral valaciclovir [abstract]. J Europ Acad Dermat Venereol 1995; 5 Suppl. 1: no. P187, S162.Google Scholar
- 54.Woolley P, Crooks RJ, The International Valaciclovir HSV Group. Prevention of vesicular lesions in recurrent genital herpes with oral valaciclovir. 1st European Congress of Chemotherapy. 1996 May 14–17; Glasgow, W117Google Scholar
- 55.Aoki F. Valtrex (valaciclovir) for the treatment of recurrent genital herpes. Can J Infect Dis. 1995 Jul; 6: 287C.Google Scholar
- 59.Patel R, Crooks RJ, Bell AR, et al. Once-daily valaciclovir for suppresion of recurrent genital herpes — the first placebo-controlled clinical trial. 1st European Congress of Chemotherapy. 1996 May 14–17, GlasgowGoogle Scholar
- 60.Drucker JL, Miller JM, International Valaciclovir HSV Study Group. Once-daily valaciclovir sustains the suppressive efficacy and safety record of aciclovir in recurrent genital herpes. European Congress of Chemotherapy. 1996 May 14–17; Glasgow, W118Google Scholar
- 61.Feinberg J, Cooper D, Hurwitz S. Phase III study of valaciclovir (VACV) for cytomegalovirus (CMV) prophylaxis in patients with advanced HIV disease [abstract]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1995 Sep 17–20; San Francisco, 243Google Scholar
- 62.Feinberg J, Cooper D, Hurwitz S. Phase III International Study of Valaciclovir (VACV) for cytomegalovirus (CMV) prophylaxis in patients with advanced HIV disease. 11th International Conference on AIDS. 1996 Jul 7–12; Vancouver, 225.Google Scholar
- 64.Mortality Morbidity Weekly Report. 1993 Oct 22; 42 (41): 306Google Scholar
- 65.Glaxo Wellcome. Valaciclovir Prescribing Information. UK, Nov 1995Google Scholar
- 66.Conlon CP. Herpes Zoster. Prescr J 1995; 35(2): 46–52Google Scholar
- 67.Hong W, Cousins M. Postherpetic neuralgia: Is it preventable and treatable? Mod Med Aust 1996; 39(3): 84–7Google Scholar
- 70.Beauchamp LM, Krenitsky TA. Acyclovir prodrugs: the road to valaciclovir. Drugs Future 1993 Jul; 18: 619–28Google Scholar