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Tecarfarin, a Novel Vitamin K Reductase Antagonist, Is Not Affected by CYP2C9 and CYP3A4 Inhibition Following Concomitant Administration of Fluconazole in Healthy Participants
Author(s) -
Bavisotto Linda M.,
Ellis David J.,
Milner Peter G.,
Combs Daniel L.,
Irwin Ian,
Canafax Daniel M.
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010370588
Subject(s) - fluconazole , pharmacokinetics , warfarin , pharmacology , bioequivalence , cmax , medicine , drug interaction , cyp2c9 , bioavailability , vitamin k antagonist , cytochrome p450 , antifungal , dermatology , metabolism , atrial fibrillation
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.