Viramidine demonstrates better safety than ribavirin in monkeys but not rats.
The safety of viramidine was evaluated and compared with ribavirin in one-month and six-month studies in rats and one-month and nine-month studies in monkeys. Viramidine administration produced hemolytic anemia, characterized by decreases in hemoglobin (Hgb) concentrations, which was accompanied by erythroid hyperplasia of the bone marrow or increase in reticulocyte counts. In the 1-month study in rats, viramidine or ribavirin dosing at 120 mg/kg/day reduced Hgb concentrations (12-16% and 13-20% compared to controls, respectively) and caused slight erythroid hyperplasia in the bone marrow. In the 6-month study in rats, viramidine or ribavirin dosing at 90 mg/kg/day reduced Hgb concentrations (16-18% and 18% compared to controls, respectively) and increased reticulocyte counts (>25%). Although toxicity effects in monkeys were similar to rats, they occurred at higher doses of viramidine compared to ribavirin. In the 1-month monkey study, viramidine at 600 mg/kg/day caused slight or no reduction (9%-0% in males and females) in Hgb concentrations compared to moderate reduction for ribavirin at 300 mg/kg/day (14%-20% in males and females). There were no signs of erythroid hyperplasia in bone marrow or significant increase in reticulocytes detected after viramidine or ribavirin dosing in monkeys. In the 9-month study in monkeys, viramidine at 180 mg/kg/day slightly reduced Hgb concentrations (5-11%) as compared to ribavirin at 60 mg/kg/day (9-12%). Both treatments had an increase in reticulocytes (49-53% vs. 43-59% compared to controls, respectively). Moderate decrease in Hgb levels (26-29%) together with large increase in reticulocyte counts (203-224%) were seen for viramidine at 600 mg/kg/day. All the changes were reversible after a recovery phase in both rats and monkeys. It is concluded that ribavirin and viramidine produced similar toxicity in rats. However, viramidine is safer than ribavirin in monkeys.
Research and Development, Valeant Pharmaceuticals International, Costa Mesa, California 92626, USA. sdadgostari@valeant.com
Soheila
S
Dadgostari
Christine
C
Xu
Li-Tain
LT
Yeh
Chin Chung
CC
Lin
Domenico
D
Vitarella
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D001772:Blood Cell Count; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D005128:Eye Diseases / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics / Q000187:drug effects; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*
D000998:Antiviral Agents; D012254:Ribavirin; C026956:taribavirin