Hepatitis C virus (HCV) infection produces cirrhosis, end-stage liver disease and liver cancer and by 2010 38,000 deaths will result from infection. The current standard of care for chronic HCV infection is a combination of an interferon-alpha product and ribavirin however under-use of available treatments as well as anemia associated with ribavirin represents a serious problem (for further information see our feature "Pipeline Insight: Hepatitis C"). Even so, worldwide sales of ribavirin totalled approximately $1.2 billion in 2002. Opportunities for prodrugs of ribavirin are immense both in terms of patient care and pharmaceutical revenue. Valeant have developed a prodrug of ribavirin, viramidine which is activated within the liver resulting in reduced levels of ribavirin accumulating in red blood cells. The present phase I study of viramidine demonstrates the excellent absorption and activation of oral viramidine. Although treatment with viramidine resulted in the accumulation of ribavirin in the plasma and red blood cells viramidine displayed good tolerability and infrequent hemolysis. Since a phase II study has been successfully completed demonstrating reduced anemia but equal efficacy with viramidine compared to ribavirin and phase III studies have now been initiated

Hepatitis C virus (HCV) infection causes inflammation of the liver and degradation of liver function. Approximately 70% of individuals infected with HCV progress to chronic hepatitis. Up to 20% develop cirrhosis and as many as 1% progress to end-stage liver disease or liver cancer in their lifetime. In total, HCV infection causes 10,000 to 12,000 deaths a year in the US increasing to 38,000 by the year 2010.

The current standard of care for chronic HCV infection is a combination of an interferon-alpha product and ribavirin. However only 80,000 patients in the United States receive treatment for HCV infection (for further information see our feature "Pipeline Insight: Hepatitis C"). In spite of the current low penetration rate of existing drugs, sales of treatments for HCV infection are large with, for example, worldwide sales of ribavirin totalling approximately $1.2 billion in 2002. Sales of HCV drugs are expected to grow due to improved market penetration through increased awareness and improved diagnosis rates and therapies.

The therapeutic window of treatments for hepatitis is currently suboptimal; both ribavirin and Hepsera, a second line adefovir prodrug treatment of HBV, have significant toxicities. LeadDiscovery has recently featured work conducted by California-based Valeant Pharmaceuticals which has resulted in the development of an improved adefovir prodrug (remofovir mesylate) for the treatment of HBV infection (click here for editorial). Valeant’s focus is on the development of prodrugs that are activated by liver-specific enzymes allowing hepatic targeting of active drug. In the case of remofovir mesylate, activation of the prodrug to PMEA is driven by cytochrome P4503A4, which is predominantly present in the liver.

Here we highlight the optimization of ribavirin for the treatment of HCV infection. Although the combination of ribavirin and peginterferon alfa achieves sustained viral responses in more than 50% percent of hepatitis C patients, it can be associated with dose-limiting anemia. This effect arises from the erythrocytic uptake and phosphorylation of ribavirin. Red blood cells are however unable to dispose of these metabolites which become effectively trapped. Anemia often prompts ribavirin dose reduction or discontinuation, and since adherence to therapy has been shown to play a major role in achieving a sustained viral response this adverse effect can seriously undermine the benefit experienced by patients.

Viramidine is a synthetic nucleoside (guanosine) analog under development for the treatment of patients with chronic hepatitis C. This orally active ribavirin prodrug is taken up and activated by adenosine deaminase within the liver. This results in much better targeting of ribavirin to the liver with the potential for an improved safety margin. A phase I pharmacokinetics and safety study of viramidine in healthy volunteers was reported in 2004. Since hepatitis infection compromises liver function and because the live is the site of viramidine activation similar studies were required in HCV infected patients. The study featured here is an ascending multiple-dose pharmacokinetic study of viramidine in this target population.

Twenty four patients were divided into three treatment groups each receiving a different dose (400, 600 & 800mg) of oral viramidine bid for 28 days. Aora et al report in this month’s J Clin Pharmacol that viramidine was rapidly absorbed throughout the study and that the ratios of plasma ribavirin AUC(0-12hrs) to plasma viramidine AUC(0-12hrs) after 28 days (ie under steady state conditions) was 6.5-8.3. This ratio confirms that the excellent bioconversion of viramidine seen in healthy individuals was replicated in HCV-infected patients. The levels of viramidine and ribavirin in the plasma and red blood cells increased on raising the dose of viramidine from 400 to 600mg although no further changes were observed upon increasing the dose to 800mg. This indicates that the bioactivation of viramidine is saturatable, a factor that along with its tolerability profile is important in terms of dose selection. A far as tolerability is concerned although ribavirin did accumulate in the plasma and red blood cells the authors conclude that accumulation was less than for with ribavirin dosing. This is reflected by the tolerability of viramidine in this study and the infrequency of hemolysis.

Since the completion of this pharmacokinetic study a phase II study of 180 treatment-naive subjects with chronic HCV was initiated (2003). The study included 4 treatment groups: viramidine (400, 600 and 800 mg bid) and ribavirin 1000/1200 mg daily all in combination with peginterferon alfa-2a. The end-of-treatment analysis was conducted to determine the incidence of anemia and also HCV RNA levels. Fewer patients developed anemia in the viramidine arms than in the ribavirin arm (4 vs 27%). Differences noted in efficacy were not statistically significant between the viramidine arms versus ribavirin. Valeant have now initiated two phase III studies of viramidine with the chose fixed at 600mg BID. These trials known as VISER1 and VISER2 (VIramidine's Safety and Efficacy vs. Ribavirin), are being conducted at approximately 100 sites worldwide and with approximately 1,000 patients in each study. VISER1 (initiated 2003) compares viramidine to ribavirin, in combination with Schering-Plough's Peg-Intron. VISER2 (initiated 2004) compares viramidine to ribavirin, in combination with Roche's Pegasys.

Entry date Thursday, June 02, 2005

J Clin Pharmacol. 2005 Mar;45(3):275-85.

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