Valaciclovir:development, clinical utility and potential

Abstract

Valaciclovir (Valtrex™, Zelitrex™), the L-valine ester of aciclovir, increases aciclovir bioavailability by 3- to 5-fold over that achievable with oral aciclovir. It addresses many unmet needs of currently available anti-herpesvirus therapies. Valaciclovir extends the efficacy of aciclovir in the treatment of herpes zoster and genital HSV infections, using less frequent dose regimens but retaining the highly acceptable safety profile established for aciclovir. The potential for valaciclovir in CMV prophylaxis has now been proven, and further refining to identify the optimal dose regimen is ongoing. After oral administration, valaciclovir is rapidly absorbed and extensively converted to aciclovir and L-valine, the essential amino acid. The mode of action and spectrum of antiviral activity of valaciclovir are thus identical to aciclovir. The bioavailability of aciclovir after valaciclovir, characterised from studies in healthy adult volunteers, is similar in a wide range of patient populations, including the elderly, those with advanced HIV disease, patients with impaired liver or renal function, or undergoing bone marrow transplantation. No clinically significant drug interactions with valaciclovir have so far been identified. Dosage reductions in clinical use of valaciclovir are only necessary when renal function is severely impaired. In controlled clinical trials in herpes zoster, valaciclovir (1000 mg three times daily) is superior to aciclovir in speeding the resolution of zoster-associated pain and post-herpetic neuralgia. It is as effective as aciclovir in hastening rash healing. In patients with ophthalmic zoster, no differences were evident between valaciclovir and aciclovir treatment on zoster-associated pain or the occurrence of ocular complications. The safety profiles of valaciclovir, aciclovir and placebo were not different in this study programme. In a series of controlled, randomised trials of valaciclovir, aciclovir and placebo for the acute treatment of genital HSV infections in approximately 3000 patients, twice daily valaciclovir was proven as effective as the standard 5 times daily aciclovir regimen in resolving the clinical signs and symptoms of lesional disease. Early patient-initiated valaciclovir therapy (500 mg twice daily) of recurrent genital herpes episodes was shown significantly to increase the chance of prevention of vesicular or ulcerative lesions, a valuable clinical advantage not prospectively proven for aciclovir. When used for periods of up to one year, valaciclovir (500 mg once daily) effectively suppresses genital herpes recurrences. Long-term studies of valaciclovir for HSV suppression, evaluating doses of up to 1000 mg daily in approximately 3000 patients, about 25% of whom were HIV seropositive (CD+ >> 100 cells/μl), revealed a highly acceptable clinical tolerability profile for valaciclovir that did not differ from aciclovir or placebo. There were no cases resembling thrombotic microangiopathy in these long-term studies. The aciclovir safety heritage and pharmacokinetic rationale for the development of valaciclovir have been realised through the clinical research programmes in the zoster and HSV indications. Further studies in these and related areas, including CMV prophylaxis, are in progress and aim to expand further the clinical potential of valaciclovir in the future.