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

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. T he pharmacokinetics of this drug candidate were evaluated following its int ravenous (i.v.) or oral (p.o.) administration as a solution in hydroxypropy l-beta-cyclodextrin (HP beta CD) or oral administration as a suspension in 0.4% methylcellulose (MC) in studies involving mice, rats, rabbits, dogs, a nd cynomolgus monkeys. SCH 56592 was orally bioavailable in all species. Th e oral bioavailability was higher with the HP beta CD solution (range, 52 t o similar to 100%) than from the MC suspension (range, 14 to 48%) and was h igher 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]) t han in monkeys (52% [HP beta CD] and 14% [MC]). In rabbits, high concentrat ions in serum suggested good oral bioavailability with the MC suspension. T he 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 giv en increasing oral doses (mice, rats, and dogs), serum drug concentrations were dose related. Food produced a fourfold increase in serum drug concentr ations in dogs. Multiple daily doses of 40 mg of SCH 56592/kg of body weigh t for eight consecutive days to fed dogs resulted in higher concentrations in serum, indicating accumulation upon multiple dosing, with an accumulatio n index of approximately 2.6. Concentrations above the MICs and minimum fun gicidal 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 fo r mice, rats, and rabbits and 10 mg/kg for dogs and monkeys), suggesting th at once-daily administration of SCH 56592 in human subjects would be a ther apeutically effective dosage regimen.