7th International AIDS Conference Florence, Italy — June 16-21, 1991

Int Conf AIDS 1991 Jun 16-21; 7:100 (abstract no. M.A.1032)
Johnson D, Dougherty WJ, Pool W, Riley MG, Yacobi A; American Cyanamid Company, Pearl River, New York, USA

OBJECTIVE: To investigate interspecies differences in the toxicokinetics of FLT.

METHODS: The comparative toxicokinetics of FLT in the rat and dog was evaluated in studies supported by pharmacokinetics, hematology and pathology. In monkeys, a study focusing on hematology and pharmacokinetics was conducted.

RESULTS: In rats, the AUC and Cmax of FLT increased with increasing oral doses (25 to 1000 mg/kg). The elimination half-life was approximately 2 hours. At 25 mg/kg for 30 days, Cmax of 11 mug/ml was associated with decreases in RBC's. In dogs, the AUC and Cmax of FLT also increased with increasing oral doses (5 mg/kg to 1000 mg/kg). The elimination half-life ranged from 1.8 to 2.8 hours over the dosage range studied. At 5 mg/kg for 30 days, WBC's and platelets were decreased. Their effects were associated with a Cmax of 5.3 mug/ml. In monkeys, Cmax and AUC values increased with increasing doses (1 to 100 mg/kg/day). The elimination half-life ranged from 1 to 1.6 hours. A linear relationship indicated that between percent erythrocytes reduction and log AUC, an AUC of 70 mug hr/ml was associated with a 25% reduction in erythrocytes. Further, in rats and dogs peak plasma concentrations and half-lives were similar for both FLT and AZT when given at equal doses. In the cynomolgus monkey, FLT plasma concentrations and AUC values were 2-3 fold higher, and elimination half-lives were longer (1 to 1.6 hours) than those of AZT (0.6 to 0.7 hours).

CONCLUSIONS: An analysis of toxicokinetic data showed a strong relationship between plasma levels of FLT and toxicity in three laboratory animal species.

Copyright © 1991 - International AIDS Society (IAS). Reproduction of this abstract (other than one copy for personal reference) must be cleared through the IAS.