title: Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants.
abstract: Comparative pharmacokinetics of vitamin K epoxide reductase antagonists tecarfarin and warfarin were assessed before and after coadministration for 21 days of the CYP450 inhibitor fluconazole in a randomized, open-label, single-center drug interaction study. Twenty healthy adult participants were randomized 1:1 to receive approximately equipotent single oral doses of tecarfarin (50 mg) or warfarin (17.5 mg). Following 7 days of baseline serial blood level collections, each participant received oral fluconazole 400 mg daily for 21 days. A second identical single oral dose of tecarfarin or warfarin was given 14 days after starting fluconazole with serial pharmacokinetic sampling. Key pharmacokinetic parameters C(max), t(max), AUC(0-168), apparent clearance, and t(1/2) demonstrated no tecarfarin-fluconazole interaction but a strong warfarin-fluconazole interaction. The ratio of log-transformed mean AUC(0-168) with versus without fluconazole for tecarfarin was 91.2% (90% confidence interval [CI]: 83.3-99.8) and for racemic warfarin was 213% (90% CI: 202-226). The 90% CI was entirely within the standard 80% to 125% bioequivalence interval for tecarfarin but well outside the bioequivalence interval for warfarin, confirming a clinically significant pharmacokinetic interaction between warfarin and fluconazole. In contrast, tecarfarin pharmacokinetics were apparently unchanged by fluconazole.
authors.affiliation: Charles River Laboratories Clinical Services Northwest, in Tacoma, Washington, USA. Linda.Bavisotto@gmail.com
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bavisotto
authors.forename: David J
authors.initials: DJ
authors.lastname: Ellis
authors.forename: Peter G
authors.initials: PG
authors.lastname: Milner
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Combs
authors.forename: Ian
authors.initials: I
authors.lastname: Irwin
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Canafax
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003374:Coumarins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D006801:Humans; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005466:Fluorocarbons
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D001565:Benzoates; D003374:Coumarins; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D015725:Fluconazole; D016660:NAD(P)H Dehydrogenase (Quinone); D014859:Warfarin; C450260:CYP2C9 protein, human; C510163:CYP3A4 protein, human; C547288:tecarfarin; D005466:Fluorocarbons