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The pharmacokinetics of darexaban (YM150), an oral direct factor Xa inhibitor, are not affected by ketoconazole, a strong inhibitor of CYP3A and P‐glycoprotein
Author(s) -
Groenendaal Dorien,
Strabach Gregory,
GarciaHernandez Alberto,
Kadokura Takeshi,
Heeringa Marten,
Mol Roelof,
Eltink Charlotte,
Onkels Hartmut
Publication year - 2014
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.93
Subject(s) - ketoconazole , medicine , pharmacokinetics , pharmacology , cmax , crossover study , enterohepatic circulation , active metabolite , metabolite , placebo , metabolism , antifungal , alternative medicine , pathology , dermatology
We investigated the effects of ketoconazole on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite darexaban glucuronide (YM‐222714) which almost entirely determines the antithrombotic effect. In this open‐label, randomized, two‐period crossover study, 26 healthy male volunteers received in one treatment period a single dose of darexaban 60 mg, and in the other treatment period, ketoconazole 400 mg once daily on Days 1–9 with a single dose of darexaban 60 mg on Day 4. Washout between periods was at least 1 week. The geometric mean ratio (90% confidence interval) of darexaban glucuronide (darexaban plus ketoconazole versus darexaban) for AUC inf was 1.11 (1.00, 1.23), and for C max 1.18 (1.03, 1.35). Darexaban concentrations remained very low (AUC last ∼196‐fold lower) in relation to darexaban glucuronide concentrations. In conclusion, the PK of darexaban glucuronide was not affected to a clinically relevant degree by co‐administration of the strong CYP3A/P‐glycoprotein inhibitor, ketoconazole. The PK of the parent compound darexaban were changed, however, concentrations remained quantitatively insignificant in relation to the main active moiety, darexaban glucuronide.