Clinical Pharmacology, Akros Pharma Inc., Princeton, New Jersey, USA.
Clinical Pharmacology, Pharmaceutical Division, Japan Tobacco Inc., Tokyo, Japan.
Clin Pharmacol Drug Dev. 2023 Jul;12(7):683-690. doi: 10.1002/cpdd.1252. Epub 2023 May 19.
The pharmacokinetics of enarodustat were elucidated in healthy subjects and in patients with end-stage renal disease (ESRD) on hemodialysis in phase 1 studies conducted in the United States and Japan. In healthy non-Japanese and Japanese subjects, following single oral administration up to 400 mg, enarodustat was rapidly absorbed. Maximum plasma concentration and area under the plasma concentration-time curve from the time of dosing to infinity were dose-dependent, renal excretion of unchanged enarodustat was substantial (on average ≈45% of dose), and mean t of <10 hours indicated negligible accumulation with once-daily dosing. In general, with daily dosing (25, 50 mg), accumulation at steady-state was ≈1.5-fold (t ≈15 hours), presumably due to a decrease in renal drug excretion which is not clinically relevant in patients with ESRD. In the single- and multiple-dose studies, plasma clearance (CL/F) was lower in healthy Japanese subjects. In non-Japanese patients with ESRD on hemodialysis, following once-daily dosing (2-15 mg), enarodustat was rapidly absorbed, steady-state maximum plasma concentration and area under the plasma concentration-time curve during the dosing interval were dose-dependent, and interindividual variability in the exposure parameters was low-to-moderate (coefficient of variation, 27%-39%). Steady-state CL/F was similar across doses, renal drug excretion was not significant (<10% of dose), mean t and t were similar (overall, 8.97-11.6 hours), and accumulation was minimal (≈20%), demonstrating predictable pharmacokinetics. Japanese patients with ESRD on hemodialysis (15 mg, single dose) exhibited similar pharmacokinetics with mean t of 11.3 hours and low interindividual variability in the exposure parameters, albeit with lower CL/F versus non-Japanese patients. Body weight-adjusted clearance values were generally similar in non-Japanese and Japanese healthy subjects and also in patients with ESRD on hemodialysis.
在 1 期研究中，在美国和日本进行的健康受试者和接受血液透析的终末期肾病（ESRD）患者中阐明了恩拉司他特的药代动力学。在健康的非日本和日本受试者中，单次口服高达 400mg 后，恩拉司他特迅速被吸收。最大血浆浓度和从给药时间到无穷大的血浆浓度-时间曲线下面积与剂量呈依赖性，未改变的恩拉司他特的肾排泄量相当大（平均约为剂量的 45%），平均 t1/2 约为 10 小时，表明每日一次给药时几乎没有蓄积。一般来说，每日给药（25、50mg）时，稳态时的蓄积约为 1.5 倍（t1/2 约为 15 小时），可能是由于肾药物排泄减少所致，这在 ESRD 患者中无临床意义。在单次和多次剂量研究中，健康日本受试者的血浆清除率（CL/F）较低。在接受血液透析的非日本 ESRD 患者中，每日一次给药（2-15mg）后，恩拉司他特迅速被吸收，稳态时最大血浆浓度和给药间隔内的血浆浓度-时间曲线下面积与剂量呈依赖性，暴露参数的个体间变异性较低至中等（变异系数为 27%-39%）。稳态时 CL/F 与剂量相似，肾药物排泄不显著（<10%的剂量），平均 t1/2 和 t1/2 相似（总体为 8.97-11.6 小时），蓄积最小（约 20%），表明药代动力学可预测。接受血液透析的日本 ESRD 患者（单次剂量 15mg）表现出相似的药代动力学，平均 t1/2 为 11.3 小时，暴露参数的个体间变异性较低，但与非日本患者相比，CL/F 较低。非日本健康受试者和接受血液透析的 ESRD 患者的体重校正清除率值通常相似。
