title: Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor.
abstract: Asunaprevir (ASV; BMS-650032), a low nanomolar inhibitor of the hepatitis C virus (HCV) NS3 protease, is currently under development, in combination with other direct-acting antiviral (DAA) agents for the treatment of chronic HCV infection. Extensive nonclinical and pharmacokinetic studies have been conducted to characterize the ADME properties of ASV. ASV has a moderate to high clearance in preclinical species. In vitro reaction phenotyping studies demonstrated that the oxidative metabolism of ASV is primarily mediated via CYP3A4; however, studies in bile-duct cannulated rats and dogs suggest that biliary elimination may contribute to overall ASV clearance. ASV is shown to have hepatotropic disposition in all preclinical species tested (liver to plasma ratios >40). The translation of in vitro replicon potency to clinical viral load decline for a previous lead BMS-605339 was leveraged to predict a human dose of 2 mg BID for ASV. Clinical drug-drug interaction (DDI) studies have shown that at therapeutically relevant concentrations of ASV the potential for a DDI is minimal. The need for an interferon free treatment combined with ASV's initial clinical trial data support development of ASV as part of a fixed dose combination for the treatment of patients chronically infected with HCV genotype 1.
authors: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Kathleen W
authors: KW
authors: Mosure
authors: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Jay O
authors: JO
authors: Knipe
authors: Department of Bioanalytical Research, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Marc
authors: M
authors: Browning
authors: Department of Biotransformation, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Vinod
authors: V
authors: Arora
authors: Department of Biotransformation, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Yue-Zhong
authors: YZ
authors: Shu
authors: Department of Biotransformation, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Thomas
authors: T
authors: Phillip
authors: Department of Virology, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Fiona
authors: F
authors: Mcphee
authors: Department of Medicinal Chemistry, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Paul
authors: P
authors: Scola
authors: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Anand
authors: A
authors: Balakrishnan
authors: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Matthew G
authors: MG
authors: Soars
authors: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Kenneth
authors: K
authors: Santone
authors: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Wallingford, Connecticut.
authors: Michael
authors: M
authors: Sinz
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004285:Dogs; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; 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
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000998:Antiviral Agents; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D007546:Isoquinolines; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C571889:asunaprevir
keywords: ADME; P-glycoprotein; antiinfectives; bioavailability; clearance; disposition; hepatic clearance; in vitro/in vivo correlations (IVIVC); metabolism; pharmacokinetics