title: The pharmacokinetics of darexaban (YM150), an oral direct factor Xa inhibitor, are not affected by ketoconazole, a strong inhibitor of CYP3A and P-glycoprotein.
abstract: 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 AUCinf was 1.11 (1.00, 1.23), and for Cmax 1.18 (1.03, 1.35). Darexaban concentrations remained very low (AUClast ∼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.
authors.affiliation: Astellas Pharma Global Development Europe, Leiden, The Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Groenendaal
authors.affiliation: Life Science Services Clinical Research, SGS, Paris, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Strabach
authors.affiliation: Astellas Pharma Global Development Europe, Leiden, The Netherlands.
authors.forename: Alberto
authors.initials: A
authors.lastname: Garcia-Hernandez
authors.affiliation: Astellas Pharma, Inc., Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kadokura
authors.affiliation: Astellas Pharma Global Development Europe, Leiden, The Netherlands.
authors.forename: Marten
authors.initials: M
authors.lastname: Heeringa
authors.affiliation: Astellas Pharma Global Development Europe, Leiden, The Netherlands.
authors.forename: Roelof
authors.initials: R
authors.lastname: Mol
authors.affiliation: Astellas Pharma Global Development Europe, Leiden, The Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Eltink
authors.affiliation: Astellas Pharma Global Development Europe, Leiden, The Netherlands.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Onkels
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D019540:Area Under Curve; D001381:Azepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004347:Drug Interactions; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005602:France; D020719:Glucuronides / Q000493:pharmacokinetics; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000935:Antifungal Agents; D001381:Azepines; D001549:Benzamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D065427:Factor Xa Inhibitors; D020719:Glucuronides; C570990:darexaban glucuronide; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C569750:darexaban; D007654:Ketoconazole
keywords: CYP3A; P-glycoprotein; YM150; anticoagulant; darexaban; factor Xa inhibitor; ketoconazole; pharmacokinetics