title: Effect of casopitant, a novel NK-1 receptor antagonist, on the pharmacokinetics and pharmacodynamics of steady-state warfarin.
abstract: Casopitant, a novel NK-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, is a weak to moderate inhibitor of CYP3A and a moderate inducer of CYP2C9 in vitro. Furthermore, both CYP enzymes are involved in the metabolism of R- and S-warfarin, respectively. This clinical study was conducted to explore the potential drug-drug interaction between casopitant and warfarin. In total, 97 healthy participants were enrolled and 54 completed the study. Participants received individualized daily dosing of warfarin to an international normalized ratio (INR) of 1.3 to 2.3 over a 14-day period (period 1). Immediately following period 1, participants entered period 2 and were randomized to receive either regimen A (oral casopitant [150 mg day 1, 50 mg days 2 and 3] and warfarin [days 1-10]) or regimen B (oral casopitant 60 mg and warfarin [days 1-14]). INR assessments were performed daily. The steady-state C(max) and AUC of R- and S-warfarin were not altered by regimen A, but R-warfarin AUC was increased 1.31-fold (90% confidence interval [CI]: 1.22, 1.41), and S-warfarin AUC was increased 1.27-fold (90% CI: 1.18, 1.38) on day 14 in regimen B. Steady-state INR values were not affected by either casopitant regimen.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC 27709, USA. lyndon.c.kirby@gsk.com
authors.forename: Lyndon C
authors.initials: LC
authors.lastname: Kirby
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Johnson
authors.forename: Laurel M
authors.initials: LM
authors.lastname: Adams
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Eberwein
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Murray
authors.forename: Christian D
authors.initials: CD
authors.lastname: Lates
authors.forename: Robert A
authors.initials: RA
authors.lastname: Blum
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Morris
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology; D000932:Antiemetics / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D013237:Stereoisomerism; D013997:Time Factors; D014859:Warfarin / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult; D014508:Urea
chemical_list: D000925:Anticoagulants; D000932:Antiemetics; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; D014859:Warfarin; C531951:casopitant; D014508:Urea