Pharmacokinetics of SCH 56592, a new azole broad-spectrum antifungal agent, in mice, rats, rabbits, dogs, and cynomolgus monkeys

被引:61
作者
Nomeir, AA
Kumari, P
Hilbert, MJ
Gupta, S
Loebenberg, D
Cacciapuoti, A
Hare, R
Miller, GH
Lin, CC
Cayen, MN
机构
[1] Schering Plough Corp, Res Inst, Dept Drug Metab & Pharmacokinet, Kenilworth, NJ 07033 USA
[2] Schering Plough Corp, Res Inst, Dept Biotechnol, Kenilworth, NJ 07033 USA
[3] Schering Plough Corp, Res Inst, Dept Chemotherapy & Mol Genet, Kenilworth, NJ 07033 USA
关键词
D O I
10.1128/AAC.44.3.727-731.2000
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
SCH 56592 is a new broad-spectrum azole antifungal agent that is in phase 3 clinical trials for the treatment of serious systemic fungal infections. The pharmacokinetics of this drug candidate were evaluated following its intravenous (i.v.) or oral (p.o.) administration as a solution in hydroxypropyl-beta-cyclodextrin (HP beta CD) or oral administration as a suspension in 0.4% methylcellulose (MC) in studies involving mice, rats, rabbits, dogs, and cynomolgus monkeys. SCH 56592 was orally bioavailable in all species. The oral bioavailability was higher with the HP beta CD solution (range, 52 to similar to 100%) than from the MC suspension (range, 14 to 48%) and was higher in mice (similar to 100% [HP beta CD] and 47% [MC]), rats (similar to 66% [HP beta CD] and 48% [MC]), and dogs (72% [HP beta CD] and 37% [MC]) than in monkeys (52% [HP beta CD] and 14% [MC]). In rabbits, high concentrations in serum suggested good oral bioavailability with the MC suspension. The i.v. terminal-phase half-lives were 7 h in mice and rats, 15 h in dogs, and 23 h in monkeys. In rabbits, the oral half-life was 9 h. In species given increasing oral doses (mice, rats, and dogs), serum drug concentrations were dose related. Food produced a fourfold increase in serum drug concentrations in dogs. Multiple daily doses of 40 mg of SCH 56592/kg of body weight for eight consecutive days to fed dogs resulted in higher concentrations in serum, indicating accumulation upon multiple dosing, with an accumulation index of approximately 2.6. Concentrations above the MICs and minimum fungicidal concentrations for most organisms were observed at 24 h following a single oral dose in MC suspension in all five species studied (20 mg/kg for mice, rats, and rabbits and 10 mg/kg for dogs and monkeys), suggesting that once-daily administration of SCH 56592 in human subjects would be a therapeutically effective dosage regimen.
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页码:727 / 731
页数:5
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