title: The Hypoxia-inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) and Warfarin in Healthy Volunteers: A Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction Study.
abstract: Roxadustat is a small-molecule hypoxia-inducible factor prolyl-hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in patients with chronic kidney disease (CKD). Warfarin is an oral anticoagulant with a narrow therapeutic window that is often prescribed to treat coexisting cardiovascular diseases in patients with CKD. This clinical trial was designed to evaluate the effect of roxadustat on warfarin pharmacokinetic and pharmacodynamic parameters.
  
  
  
  This open-label, single-sequence crossover study was conducted in healthy volunteers (male or female) aged 18 to 55 years with a body mass index of 18.5 to 30.0 kg/m(2). The study consisted of 2 periods separated by a minimum washout period of 14 days. After an overnight fast, volunteers received a single oral dose of 25 mg (5 × 5 mg tablets) warfarin on Day 1 of Period 1 and Day 7 of Period 2. Volunteers received oral doses of 200 mg (2 × 100 mg tablets) roxadustat on Days 1, 3, 5, 7 (concomitant with warfarin), 9, 11, 13, and 15 of Period 2. Plasma S- and R-warfarin (unbound and total concentrations) and prothrombin time were determined at multiple time points up to 216 hours postdose. Pharmacokinetic and pharmacodynamic parameters were estimated via noncompartmental methods. Tolerability was evaluated by monitoring adverse events, laboratory assays, vital signs, and 12-lead ECGs.
  
  
  
  The geometric mean ratios and 90% CIs for Cmax and AUC∞ of total and unbound S- and R-warfarin (with and without roxadustat) were within the standard bioequivalence interval of 80.00% to 125.00%. Roxadustat increased the geometric mean (GM) prothrombin (PT) and international normalized ratio (INR) AUC from time zero to last measurable sample (AUCPT,last and AUCINR,last) by 24.4%. Coadministration of roxadustat and warfarin in healthy volunteers was associated with a favorable tolerability profile, with most treatment-associated adverse events mild in severity.
  
  
  
  Based on the lack of clinically significant pharmacokinetic interactions and the limited influence on warfarin pharmacodynamic parameters, no dose adjustment of warfarin should be required when coadministered with roxadustat. ClinicalTrials.gov identifier: NCT02252731.
authors.affiliation: Astellas Pharma Europe BV, Leiden, the Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Groenendaal-van de Meent
authors.affiliation: Astellas Pharma Europe BV, Leiden, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: den Adel
authors.affiliation: Astellas Pharma Europe BV, Leiden, the Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Rijnders
authors.affiliation: Astellas Pharma Europe BV, Leiden, the Netherlands.
authors.forename: Axel
authors.initials: A
authors.lastname: Krebs-Brown
authors.affiliation: PharmAspire Consulting, Wijchen, the Netherlands.
authors.forename: Virginie
authors.initials: V
authors.lastname: Kerbusch
authors.affiliation: PAREXEL International GmbH, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Golor
authors.affiliation: Astellas Pharma Europe BV, Leiden, the Netherlands. Electronic address: Marloes.Schaddelee@astellas.com.
authors.forename: Marloes
authors.initials: M
authors.lastname: Schaddelee
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D007546:Isoquinolines; D014859:Warfarin; D005998:Glycine; C584543:roxadustat
keywords: anemia; chronic kidney disease; hypoxiainducible factor; roxadustat; warfarin