Clinical Pharmacology, Development, Astellas Pharma Inc., Tokyo, Japan.
Research Program Management, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan.
Clin Pharmacol Drug Dev. 2019 Apr;8(3):304-313. doi: 10.1002/cpdd.597. Epub 2018 Jul 2.
Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open-label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat. Subjects in the food effect study received a single dose of 100-mg roxadustat under fed and fasted conditions. Subjects in the SCA/roxadustat drug-drug interaction study received a single dose of 100-mg roxadustat alone, concomitantly with SCA, and 1 and 2 hours before and after SCA to consider the real-world clinical situation and assess any potential impact of a lag time on the pharmacokinetics of roxadustat. Primary outcomes for both studies were area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of drug in blood plasma. In the food effect study (N = 16), the geometric mean ratio (fed/fasted) and 90% confidence interval for area under the concentration-time curve from the time of dosing extrapolated to infinity and maximum concentration of roxadustat were 94.44 (89.93-99.18) and 79.88 (72.09-88.52), respectively. In the SCA/roxadustat drug-drug interaction study, all geometric mean ratios and 90% confidence intervals (roxadustat + SCA/roxadustat) were within the no-effect boundaries of 80% and 125%. Roxadustat was generally well tolerated. The effect of food on the pharmacokinetics of roxadustat and the drug-drug interaction between roxadustat and SCA do not appear to be clinically relevant and support the safe use of roxadustat under these conditions.
罗沙司他是一种低氧诱导因子脯氨酰羟化酶抑制剂，目前处于治疗慢性肾脏病贫血的临床后期开发阶段。球形碳吸附剂（SCA）用于慢性肾脏病患者，已被证明会影响某些伴随药物的吸收。两项在健康成年日本男性中进行的 1 期、开放标签、随机、交叉研究，旨在考察食物和 SCA 对单次口服罗沙司他的药代动力学的影响。在食物影响研究中，受试者在进食和禁食条件下接受单次 100mg 罗沙司他给药。在 SCA/罗沙司他药物相互作用研究中，受试者单独接受单次 100mg 罗沙司他给药，同时给予 SCA，并在给予 SCA 前 1 小时和后 2 小时给予 SCA，以考虑真实临床情况，并评估对罗沙司他药代动力学的任何潜在滞后时间的影响。这两项研究的主要终点均为从给药时间外推至无穷大的血药浓度-时间曲线下面积和血浆中药物的最大浓度。在食物影响研究（N=16）中，从给药时间外推至无穷大的血药浓度-时间曲线下面积和罗沙司他最大浓度的几何均数比值（fed/fasted）及其 90%置信区间分别为 94.44（89.93-99.18）和 79.88（72.09-88.52）。在 SCA/罗沙司他药物相互作用研究中，所有几何均数比值及其 90%置信区间（罗沙司他+SCA/罗沙司他）均在 80%和 125%的无效应界内。罗沙司他总体耐受性良好。食物对罗沙司他药代动力学的影响以及罗沙司他与 SCA 之间的药物相互作用似乎没有临床意义，支持在这些条件下安全使用罗沙司他。
