Nonclinical pharmacokinetics of BMS-292655, a water-soluble prodrug of the antifungal ravuconazole.
The phosphate ester, BMS-292655, was developed as a water-soluble prodrug of the antifungal agent, ravuconazole (BMS-207147). BMS-292655 was comparatively stable in rat, beagle dog, cynomolgus monkey and human plasma, but was hydrolysed upon incubation with liver S9 preparations from all species. The major product in rat, monkey and human S9 was BMS-207147, while in dog S9, the intermediate ester, BMS-300043, predominated. BMS-300043 itself was more stable in dog S9 than in S9 preparations from the other species. Intravenous administration of BMS-292655 to rats, beagle dogs and cynomolgus monkeys indicated species differences in the extent of formation of BMS-207147 (monkeys>rats>dogs). The lower overall generation of BMS-207147 in dogs was consistent with the presence of circulating plasma levels of BMS-300043. BMS-300043 was present in monkey plasma but not detectable in rat plasma. The conversion of BMS-292655 to BMS-207147 in the presence of human S9 indicated the potential for BMS-292655 to function as a BMS-207147 prodrug in humans. The similarity in the hydrolysis of BMS-292655 when incubated with human and monkey S9 in vitro, coupled with the effective release of BMS-207147 from BMS-292655 upon i.v. administration to monkeys, is consistent with this conclusion.
Knipe
Jay O
JO
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research Institute, Wallingford, CT 06492, USA. jay.knipe@bms.com <jay.knipe@bms.com>
Mosure
Kathleen W
KW
D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D011355:Prodrugs / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013844:Thiazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D014230:Triazoles / Q000378:metabolism / Q000493:pharmacokinetics*
C533211:3-((phosphonooxy)methyl)-1-((2-(4-(4-cyanophenyl)-2-thiazolyl)-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)methyl)propoxy)methyl ester; C533212:3-(hydroxymethyl)-1-((2-(4-(4-cyanophenyl)-2-thia0zolyl)-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)methyl)propoxy)methyl ester; D000935:Antifungal Agents; D001798:Blood Proteins; D011355:Prodrugs; D013844:Thiazoles; D014230:Triazoles; C104066:ER 30346