Preclinical pharmacokinetics and in vitro metabolism of BMS-605339: a novel HCV NS3 protease inhibitor.
BMS-605339 is a potent HCV NS3 protease inhibitor that suppresses hepatitis C virus replication and was under investigation as an oral agent for the treatment of this disease. In vitro and in vivo studies were conducted in mouse, rat, dog, and monkey to characterize the pharmacokinetics and metabolism of this compound. BMS-605339 was predicted to be a moderate clearance compound in the human, based on human microsomal and hepatocyte data. Nearly all metabolism of BMS-605339 was oxidative; CYP3A4 is likely to play a key role in the metabolic clearance of this compound. Moderate to high Caco-2 permeability was observed for this compound, with the potential for P-glycoprotein involvement. The oral bioavailability of BMS-605339 was variable and dose dependent, suggesting low absorption, possibly because of transporter involvement. BMS-605339 possesses low intrinsic aqueous solubility and, in both rat and dog, administration of an aqueous suspension suggested that BMS-605339 absorption is likely solubility limited. Liver exposure of BMS-605339 was consistently higher than plasma exposure in all species tested (mouse, rat, and dog), indicating the potential for active uptake into hepatocytes. The overall preclinical pharmacokinetic profile supported the selection and development of BMS-605339 as a clinical candidate.
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Wallingford, Connecticut.
Susan
S
Jenkins
Paul
P
Scola
Fiona
F
McPhee
Jay
J
Knipe
Christoph
C
Gesenberg
Michael
M
Sinz
Vinod
V
Arora
Gary
G
Pilcher
Kenneth
K
Santone
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000493:pharmacokinetics*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D007546:Isoquinolines; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C583042:BMS-605339; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
ADME; hepatic clearance; in vitro/in vivo correlations (IVIVC); metabolism; preclinical pharmacokinetics; oral absorption; protease