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Antimicrobial Agents and Chemotherapy, March 2000, p. 727-731, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Pharmacokinetics of SCH 56592, a New Azole Broad-Spectrum Antifungal Agent, in Mice, Rats, Rabbits, Dogs, and Cynomolgus Monkeys

Amin A. Nomeir,1,* Pramila Kumari,1 Mary Jane Hilbert,2 Samir Gupta,1 David Loebenberg,3 Anthony Cacciapuoti,3 Roberta Hare,3 George H. Miller,3 Chin-Chung Lin,1 and Mitchell N. Cayen1

Departments of Drug Metabolism and Pharmacokinetics,1 Biotechnology,2 and Chemotherapy and Molecular Genetics,3 Schering-Plough Research Institute, Kenilworth, New Jersey

Received 16 February 1999/Returned for modification 20 September 1999/Accepted 24 November 1999

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 (HPbeta 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 HPbeta CD solution (range, 52 to ~100%) than from the MC suspension (range, 14 to 48%) and was higher in mice (~100% [HPbeta CD] and 47% [MC]), rats (~66% [HPbeta CD] and 48% [MC]), and dogs (72% [HPbeta CD] and 37% [MC]) than in monkeys (52% [HPbeta 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.

* Corresponding author. Mailing address: Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Mail Stop 2880, Kenilworth, NJ 07033-1310. Phone: (908) 740-3190. Fax: (908) 740-3966. E-mail: Amin.Nomeir{at}sprcorp.com.

Antimicrobial Agents and Chemotherapy, March 2000, p. 727-731, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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