Nonclinical toxicology studies with zidovudine: acute, subacute, and chronic toxicity in rodents, dogs, and monkeys.
In single dose acute toxicity studies in CD-1 mice and CD rats, the median lethal dose (MLD) for zidovudine (ZDV) was > 750 mg/kg after iv dosing and > 3000 mg/kg after po administration (recommended human dose is 100 mg every 4 hr while awake). Because of the short half-life in rats (0.8 hr), dogs (1.0 hr), and monkeys (0.8 hr), the daily dose of ZDV in most studies was given in two equal portions approximately 6 hr apart. Intravenous administration of ZDV was well tolerated in beagle dogs at dose levels up to 42.5 mg/kg bid for 2 weeks and in CD rats at dose levels up to 75 mg/kg bid for 4 weeks. In a 2-week dose range-finding study in beagle dogs, cytostatic effects were noted at po dose levels of 62.5 to 250 mg/kg bid in certain tissues with rapid cell replication rates. In contrast, in 3- to 12-month oral toxicity studies in CD rats and cynomolgus monkeys, the principal toxicologic finding was reversible macrocytic normochromic anemia which occurred at 225-250 mg/kg bid in rats and 17.5-150 mg/kg bid in monkeys. In the 12-month rat study, RBC was decreased at 25 and 75 mg/kg bid. In the 12-month monkey study WBC was slightly decreased at 150 mg/kg bid.
Ayers
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KM
Glaxo Wellcome, Inc., Research Triangle Park, North Carolina 27709, USA.
Tucker
W E
WE
Hajian
G
G
De Miranda
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P
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D005260:Female; D007262:Infusions, Intravenous; D007928:Lethal Dose 50; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D051381:Rats; D013045:Species Specificity; D015215:Zidovudine / Q000008:administration & dosage / Q000633:toxicity*
D019380:Anti-HIV Agents; D015215:Zidovudine