Toxicity of protease inhibitor KNI-272 in rats and dogs following continuous intravenous infusion or repeated iv treatment (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Toxicity of protease inhibitor KNI-272 in rats and dogs following continuous intravenous infusion or repeated iv treatment (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A2751 1994. Unique Identifier : AIDSLINE ICDB/95604436
Placke ME; Emmerling DC; Lynch ME; Graves SW; Tosca PJ; Yarrington JT; Tomaszewski JE; Battelle Columbus Laboratory, Columbus, OH 43201

Abstract: KNI-272 is a potent inhibitor of HIV protease activity (EC50 0.02-01.mm) and is being developed as a potential therapeutic agent for the treatment of AIDS. KNI-272 is not soluble in aqueous media and presented a formulation challenge in preparing suitable dosage forms. The drug was ultimately formulated in hydroxypropyl-beta-cyclodextrin (HPCD) for iv administration and a series of studies were conducted in rats and dogs evaluating the potential toxicity of this formulation at maximum achievable doses (up to 200 mg/kg/day for dogs and up to 300 mg/kg/day for rats) based on solubility and volume/rate of administration limits. Plasma drug steady state concentrations were generally dose proportional during continuous iv infusion, and dose proportional kinetics occurred following repeated iv bolus treatments in both species. In general, there were relatively few toxic effects associated directly with the drug. There were no drug-related changes in clinical pathology parameters except isolated elevations of ALP and no histopathologic changes in any of the treated dogs. Rats had body weight losses during the treatment period and showed some evidence of mild anemia and indications of mild renal toxicity. Most of these changes occurred in all dose groups including controls and were, therefore, attributed to the administration of relatively high volumes of the HPCD vehicle. There was a dose-dependent (and reversible) tubular nephrosis that was considered drug-related. Therefore, KNI-272 administered intravenously near max achievable plasma concentration (87 uM) for up to 5 days was not overtly toxic in rats or dogs.

Keywords: Animal Antineoplastic Agents/ADMINISTRATION & DOSAGE/PHARMACOKINETICS/ TOXICITY Dogs Infusions, Intravenous Oligopeptides/ADMINISTRATION & DOSAGE/PHARMACOKINETICS/*TOXICITY Rats ABSTRACT
950330
M9530842

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