title: Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug-Drug Interactions.
abstract: Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration (T max) of 2-4 h and an elimination half-life (t ½) of ≈15-20 h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4-mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of asunaprevir to the liver occurs via organic anion-transporting polypeptide (OATP)-mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug-drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.
authors.affiliation: Research and Development, Bristol-Myers Squibb, P O Box 4000, Princeton, NJ, 08543-4000, USA. timothy.eley@bms.com.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: Research and Development, Bristol-Myers Squibb, P O Box 4000, Princeton, NJ, 08543-4000, USA.
authors.forename: Tushar
authors.initials: T
authors.lastname: Garimella
authors.affiliation: Research and Development, Bristol-Myers Squibb, P O Box 4000, Princeton, NJ, 08543-4000, USA.
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
authors.affiliation: Research and Development, Bristol-Myers Squibb, P O Box 4000, Princeton, NJ, 08543-4000, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bertz
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; 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