Valganciclovir

Valganciclovir (Valcyte™) is an orally administered prodrug of the standard anti-cytomegalovirus (CMV) drug ganciclovir. Valganciclovir is as effective as intravenous ganciclovir for the treatment of AIDS-related CMV retinitis, and oral ganciclovir for the prophylaxis of CMV infection and disease in high-risk solid organ transplant recipients. The drug is generally well tolerated and has a similar tolerability profile to that of oral or intravenous ganciclovir, but is devoid of adverse events related to intravenous or indwelling catheter access associated with the use of intravenous ganciclovir, cidofovir and foscarnet. The simple and convenient once-daily valganciclovir regimen offers potential for improved patient compliance. It provides greater systemic ganciclovir exposure than oral ganciclovir, thus reducing the risk of viral resistance when used for prophylaxis in high-risk solid organ transplant recipients. Furthermore, the use of valganciclovir instead of intravenous ganciclovir may provide significant cost savings, based on data comparing oral versus intravenous regimens for the treatment of AIDS-related CMV retinitis. Overall, valganciclovir appears to have some advantages over ganciclovir. Therefore, when used as prophylaxis against CMV infection and disease in high-risk solid organ transplant recipients or as induction and maintenance therapy of CMV retinitis in patients with AIDS, oral valganciclovir is an attractive alternative to other available anti-CMV drugs.

Valganciclovir is a prodrug of an antiviral agent ganciclovir. Thus, the pharmacodynamic properties of valganciclovir are essentially those of ganciclovir. Following oral absorption, valganciclovir is rapidly and extensively converted to ganciclovir, a synthetic analogue of purine nucleoside 2′-deoxyguanosine, which inhibits the replication of herpes viruses. The activity of ganciclovir against human CMV results primarily from inhibition of viral DNA synthesis by ganciclovir triphosphate in CMV-infected human cells. In vitro and in vivo studies show that ganciclovir inhibits immune and vascular responses associated with CMV infection and/or graft rejection.

The resistance of CMV to ganciclovir most commonly results from mutations in the viral protein kinase UL97 gene responsible for monophosphorylation of ganciclovir. However, oral valganciclovir has shown low potential to cause viral resistance in patients with AIDS-related CMV retinitis and in high-risk solid organ transplant recipients.

Following oral administration, valganciclovir is well absorbed from the gastrointestinal tract and rapidly hydrolysed to ganciclovir in the intestinal wall and liver, resulting in a low and transient systemic exposure to valganciclovir. Oral valganciclovir 900mg once daily produces daily systemic exposure to ganciclovir that is 1.7-fold greater than that achieved with oral ganciclovir 1000mg three times daily, and similar to that produced with intravenous ganciclovir 5 mg/kg once daily. Ganciclovir is minimally (1–2%) bound to plasma proteins and has a large apparent volume of distribution (>120L) after administration of oral valganciclovir. Administration of valganciclovir with a high-fat meal significantly increases the area under the plasma concentration-time curve of ganciclovir compared with administration in the fasted state, without significant prolongation of time to peak plasma concentration.

Ganciclovir is the only metabolite of valganciclovir, and apart from phosphorylation in CMV-infected cells undergoes no further metabolism. Valganciclovir is eliminated from the body (as ganciclovir) almost exclusively by renal excretion, through glomerular filtration and active tubular secretion. Elimination of ganciclovir is biphasic with the mean terminal elimination half-life following oral administration of valganciclovir 900mg once daily of =4 hours in healthy volunteers or CMV- and HIV-seropositive patients and of 6.5 hours in solid organ transplant recipients.

Drug interactions associated with valganciclovir are essentially those associated with ganciclovir. Ganciclovir and zidovudine have similar potential to cause severe neutropenia and anaemia, thus commonly requiring dosage reduction when used concomitantly. Probenecid reduces renal clearance and significantly increases plasma concentrations of ganciclovir, thus concomitant administration necessitates close monitoring for ganciclovir toxicity. Coadministration of stavudine, didanosine, zalcitabine or trimethoprim with oral ganciclovir produces either no effect on ganciclovir pharmacokinetics or effects that are not likely to be of clinical significance. Metabolic drug interactions between valganciclovir and protease inhibitors or non-nucleoside reverse transcriptase inhibitors are also considered unlikely. Thus far, no clinically significant pharmacokinetic interactions between ganciclovir and the immunosuppressive drug mycophenolate mofetil have been detected. Concomitant use of ganciclovir and imipenem/cilastatin has reportedly caused convulsions and is not recommended.

The efficacy of valganciclovir has been evaluated as treatment for CMV retinitis in patients with AIDS, and as prophylaxis against CMV infection and disease in high-risk solid organ transplant recipients.

Oral valganciclovir 900mg once daily was as effective as intravenous ganciclovir 5 mg/kg once daily in the treatment of CMV retinitis in a randomised, nonblind trial in 160 patients with AIDS. During the first 4 weeks of treatment, valganciclovir arrested progression of CMV retinitis in ≥90% and achieved a satisfactory treatment response in 72% of patients with AIDS. During that time, valganciclovir also caused substantial suppression of the systemic CMV infection. In patients receiving oral valganciclovir for both induction and maintenance therapy the median time to progression of CMV retinitis was 160 days, compared with 125 days in patients receiving induction with intravenous ganciclovir and maintenance with oral valganciclovir.

Oral valganciclovir 900mg once daily and oral ganciclovir 1000mg three times daily, administered during the first 100 days post-transplant, showed similar efficacy in preventing development of CMV disease in 364 CMV seronegative recipients of heart, liver, kidney or kidney-pancreas allografts from CMV seropositive donors both during (>98% disease-free patients) and after (≥85% and ≥82% at 6 and 12 months, respectively) the treatment phase in a randomised, double-blind trial. However, in liver transplant patients, the incidence of tissueinvasive CMV disease was significantly higher in valganciclovir than in ganciclovir recipients (14% vs 3%). During prophylaxis, valganciclovir produced greater viral suppression than ganciclovir. However, the effect was offset after treatment discontinuation and was similar for both drugs at 6 and 12 months posttransplant. Patients treated with valganciclovir or ganciclovir had similar incidences of acute graft rejection, which was rarely associated with the development of CMV disease.

The tolerability profile of oral valganciclovir is essentially that of oral or intravenous ganciclovir. When used for the treatment of CMV retinitis in patients with AIDS or for prophylaxis of CMV infection in solid organ transplant recipients, valganciclovir is generally well tolerated. The most common adverse events associated with its use are neutropenia, anaemia and diarrhoea. In solid organ transplant recipients, oral valganciclovir and oral ganciclovir produced similar study-withdrawal rates (≈5%).