Groenendaal-van de Meent Dorien, den Adel Martin, Rijnders Sanne, Krebs-Brown Axel, Kerbusch Virginie, Golor Georg, Schaddelee Marloes
Astellas Pharma Europe BV, Leiden, the Netherlands.
PharmAspire Consulting, Wijchen, the Netherlands.
Clin Ther. 2016 Apr;38(4):918-28. doi: 10.1016/j.clinthera.2016.02.010. Epub 2016 Mar 4.
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.
罗沙司他是一种小分子低氧诱导因子脯氨酰羟化酶抑制剂，正处于临床开发后期，用于治疗慢性肾脏病（CKD）患者的贫血。华法林是一种口服抗凝剂，治疗窗较窄，常用于治疗CKD患者并存的心血管疾病。本临床试验旨在评估罗沙司他对华法林药代动力学和药效学参数的影响。
本开放标签、单序列交叉研究在年龄18至55岁、体重指数为18.5至30.0kg/m²的健康志愿者（男性或女性）中进行。研究包括两个阶段，间隔至少14天的洗脱期。经过一夜禁食后，志愿者在第1阶段的第1天和第2阶段的第7天接受单次口服25mg（5×5mg片剂）华法林。志愿者在第2阶段的第1、3、5、7天（与华法林同时服用）、9、11、13和15天接受口服200mg（2×100mg片剂）罗沙司他。在给药后长达216小时的多个时间点测定血浆S-和R-华法林（游离和总浓度）以及凝血酶原时间。通过非房室方法估算药代动力学和药效学参数。通过监测不良事件、实验室检测、生命体征和12导联心电图评估耐受性。
总S-和R-华法林以及游离S-和R-华法林（服用和未服用罗沙司他）的Cmax和AUC∞的几何平均比值和90%置信区间在80.00%至125.00%的标准生物等效性区间内。罗沙司他使从时间零点到最后可测量样本的凝血酶原（PT）和国际标准化比值（INR）的几何平均（GM）AUC（AUCPT,last和AUCINR,last）增加了24.4%。在健康志愿者中联合使用罗沙司他和华法林具有良好的耐受性，大多数与治疗相关的不良事件严重程度较轻。
基于缺乏具有临床意义的药代动力学相互作用以及对华法林药效学参数的影响有限，与罗沙司他合用时无需调整华法林剂量。ClinicalTrials.gov标识符：NCT02252731。
