Viramidine, a Prodrug of Ribavirin, Shows Better Liver-Targeting Properties and Safety Profiles Than Ribavirin in Animals

Abstract

Ribavirin, part of the current first line combination therapy for the treatment of chronic hepatitis C, may cause haemolytic anaemia and poses a significant challenge to the clinical management of the disease. Viramidine, a prodrug of ribavirin, is currently under development. In-vitro partition demonstrated that viramidine had less association with RBCs than ribavirin in rat, monkey and man, and thus has less liability for haemolytic anaemia than ribavirin. In a whole body autoradiography study in rats following oral dosing (30 mg/kg) of [14C]ribavirin or [14C]viramidine to monkeys, viramidine produced 32% higher radioactivity in the liver than ribavirin, indicating a better liver-targeting properties. In portal vein-cannulated cynomolgus monkeys following single oral dosing (30 mg/kg) of [3H]viramidine or [3H]ribavirin, viramidine retained 3X higher radioactivity in the liver than ribavirin. Viramidine dosing also produced a higher viramidine to ribavirin ratio in portal plasma than in systemic plasma, indicating that the liver was the main site for the viramidine conversion to ribavirin and subsequent trapping of the drug. After multiple oral dosing (10 mg/kg) of [14C]ribavirin or [14C]viramidine to monkey, viramidine yielded three times the drug level in the liver but only half in RBCs compared to ribavirin. Viramidine and ribavirin had comparable toxicity profiles in a 28-day toxicity study in rats. In contrast, viramidine had much better safety profiles than ribavirin in a 28-day toxicity study in monkeys. In conclusion, viramidine has better liver-targeting properties and safety profiles than ribavirin in animals.

Disposition and Metabolic Profiles of [ 14 C]Viramidine and [ 14 C]Ribavirin in Rat and Monkey Red Blood Cells and Liver

“…After administration of a single dose and multiple doses of viramidine, RMP, VMP, and TCONH 2 were the major radioactive components in the monkey liver ( Table 4). The total amount of ribavirin-related components (ribavirin plus RMP plus RDP plus RTP) accounted for 21.5% of the total radioactivity in the liver after administration of a single dose and 43.8% after administration of 10 daily oral doses ( (10). In the present study, very high liver radioactivity concentrations were also obtained in rats and monkeys after oral administration of [ 14 C]ribavirin or [ 14 C]viramidine.…”

The effects of HCV infection and management on health-related quality of life

“…Taribavirin (also known as viramidine; Valeant Pharmaceutical International, Costa Mesa, CA) is a liver-targeting, synthetic nucleoside (guanosine) analogue designed for the treatment of patients with CHC. 90,91 In a phase 2 study, 92 significantly fewer patients experienced anemia in the taribavirin treatment groups than in the RBV group (4% versus 27%; P Ͻ 0.0001), with no significant difference in SVR rates. In the recently completed Viramidine's (Taribavirin's) Safety and Efficacy versus Ribavirin (VISER 1) study, 91 taribavirin 600 mg twice a day or RBV 500/600 mg twice a day was given with peg-IFN alpha-2b 1.5 g/kg per week for 24 or 48 weeks.…”

Dual-Action Mechanism of Viramidine Functioning as a Prodrug and as a Catabolic Inhibitor for Ribavirin

“…1) (14). Animal studies indicate that viramidine is not efficiently taken up by RBCs like ribavirin (5). In contrast, viramidine has a better liver-targeting property and is enriched in the liver twice as much as ribavirin (13).…”