Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants

Journal of Clinical Pharmacology
Linda M BavisottoDaniel M Canafax

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 clinical...Continue Reading

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Citations

Jun 12, 2012·Advances in Therapy·Tatjana S PotparaGregory Y H Lip
Mar 1, 2012·Cardiology in Review·Abhishek MaanE Kevin Heist
Feb 28, 2016·American Heart Journal·Oliver J Ziff, A John Camm
Jan 1, 2012·Revista Brasileira De Ortopedia·Luiz Eugênio Garcez Leme, Guilherme Turolla Sguizzatto
May 20, 2014·Journal of Clinical Pharmacology·Benjamin MatagrinVirginie Lattard
Feb 10, 2017·Thrombosis and Haemostasis·Detlef AlbrechtMark G Midei
Sep 22, 2017·Thrombosis and Haemostasis·Detlef AlbrechtMark G Midei
Oct 26, 2018·Expert Opinion on Pharmacotherapy·Orsolya SzékelyGregory Yoke Hong Lip
May 24, 2016·Biopharmaceutics & Drug Disposition·Hisakazu OhtaniTakeshi Akiyoshi
Dec 12, 2017·Expert Opinion on Investigational Drugs·Gerasimos DimitropoulosGregory Y H Lip
Jul 3, 2020·International Journal of Molecular Sciences·Francesca AnnunziataAndrea Pinto

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