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Drugs

, Volume 52, Issue 5, pp 754–772 | Cite as

Valaciclovir

A Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy in Herpesvirus Infections
  • Caroline M. Perry
  • Diana Faulds
Drug Evaluation

Abstract

Synopsis

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.

Antiviral Activity

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.

Pharmacokinetic Properties

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.

Therapeutic Efficacy

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.

Tolerability

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.

Keywords

Herpes Zoster Acyclovir Genital Herpes Famciclovir Valaciclovir 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Caroline M. Perry
    • 1
  • Diana Faulds
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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