title: Pharmacokinetics of SCH 56592, a new azole broad-spectrum antifungal agent, in mice, rats, rabbits, dogs, and cynomolgus monkeys.
abstract: 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 (HPbetaCD) 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 HPbetaCD solution (range, 52 to approximately 100%) than from the MC suspension (range, 14 to 48%) and was higher in mice ( approximately 100% [HPbetaCD] and 47% [MC]), rats ( approximately 66% [HPbetaCD] and 48% [MC]), and dogs (72% [HPbetaCD] and 37% [MC]) than in monkeys (52% [HPbetaCD] 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.
authors.affiliation: Department of Drug Metabolism, Schering-Plough Research Institute, Kenilworth, New Jersey, USA. Amin.Nomeir@sprcorp.com
authors.forename: A A
authors.initials: AA
authors.lastname: Nomeir
authors.forename: P
authors.initials: P
authors.lastname: Kumari
authors.forename: M J
authors.initials: MJ
authors.lastname: Hilbert
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.forename: D
authors.initials: D
authors.lastname: Loebenberg
authors.forename: A
authors.initials: A
authors.lastname: Cacciapuoti
authors.forename: R
authors.initials: R
authors.lastname: Hare
authors.forename: G H
authors.initials: GH
authors.lastname: Miller
authors.forename: C C
authors.initials: CC
authors.lastname: Lin
authors.forename: M N
authors.initials: MN
authors.lastname: Cayen
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D018565:Food-Drug Interactions; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D014230:Triazoles / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole