title: 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.
authors.affiliation: Research and Development, Ribapharm, Costa Mesa, Calif., USA. cclin@ribapharm.com
authors.forename: Chin-chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Li-Tain
authors.initials: LT
authors.lastname: Yeh
authors.forename: Domenico
authors.initials: D
authors.lastname: Vitarella
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D016503:Drug Delivery Systems; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000882:Haplorhini; D008099:Liver / Q000378:metabolism*; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000633:toxicity; D013045:Species Specificity; D014018:Tissue Distribution; D014316:Tritium
chemical_list: D000998:Antiviral Agents; D002250:Carbon Radioisotopes; D011355:Prodrugs; D014316:Tritium; D012254:Ribavirin; C026956:taribavirin