Clinical Pharmacology, Akros Pharma, Inc., Princeton, New Jersey, USA.
Clinical Pharmacology, Pharmaceutical Division, Japan Tobacco Inc., Tokyo, Japan.
Clin Pharmacol Drug Dev. 2021 May;10(5):463-470. doi: 10.1002/cpdd.923. Epub 2021 Mar 31.
The dialysis clearance of enarodustat (JTZ-951) was determined in patients (N = 6) with end-stage renal disease on hemodialysis. Enarodustat (5 mg PO) was administered before (day 1) and after hemodialysis (day 8) with pharmacokinetic assessments on the 2 occasions. Dialysis clearance was based on plasma and dialysate enarodustat concentrations. Fraction of administered dose recovered in dialysate, total predialyzer and postdialyzer plasma enarodustat concentrations, and total and unbound venous plasma concentrations were determined. Hemodialysis did not significantly affect overall total concentrations with similar mean area under the plasma concentration-time curve from time 0 to infinity (coefficient of variation) of 3350 (26.4%) and 3640 (20.9%) ng · h/mL on days 1 and 8, respectively, and mean terminal half-life was 9.35 (11.9%) and 9.96 (18.7%) hours on the 2 occasions. Mean maximum concentration was somewhat lower on day 1 compared to day 8 (404 vs 559 ng/mL); the difference did not significantly affect total exposure (area under the plasma concentration-time curve from time 0 to infinity). Plasma protein binding was high (>99%) with similar binding on the 2 occasions, and total pre- and postdialyzer enarodustat concentrations were similar. Plasma unbound enarodustat concentrations decreased during dialysis, with a postdialysis rebound presumably due to re-equilibration with peripheral tissues. Mean unbound area under the plasma concentration-time curve from time 0 to infinity was marginally lower (∼22%) on day 1 compared to day 8. Dialysis clearance (0.415 L/h) was insignificant relative to dialyzer plasma flow (∼20 L/h), and the fraction of administered dose recovered in dialysate was small (6.74% of dose) with low intersubject variability (coefficient of variation, 14.7%). Thus, enarodustat can be administered regardless of dialysis schedule, and dose supplementation is not required in patients with end-stage renal disease on hemodialysis.
在接受血液透析的终末期肾病患者（N=6）中确定了依罗达司他（JTZ-951）的透析清除率。依罗达司他（5 毫克口服）在透析前（第 1 天）和透析后（第 8 天）给药，并在这 2 次评估药代动力学。透析清除率基于血浆和透析液中依罗达司他的浓度。从给药剂量中回收的分数在透析液中，总预透析器和后透析器血浆依罗达司他浓度，以及总和未结合的静脉血浆浓度。血液透析对总体总浓度没有显著影响，第 1 天和第 8 天的时间 0 至无穷大（变异系数）的平均血浆浓度-时间曲线下面积相似，分别为 3350（26.4%）和 3640（20.9%）ng·h/mL，平均终末半衰期分别为 9.35（11.9%）和 9.96（18.7%）小时。第 1 天的平均最大浓度与第 8 天相比略有降低（404 对 559 ng/mL）；差异未显著影响总暴露量（时间 0 至无穷大的血浆浓度-时间曲线下面积）。血浆蛋白结合率高（>99%），两次检测结果相似，且总预透析器和后透析器的依罗达司他浓度相似。在透析过程中，血浆中未结合的依罗达司他浓度下降，透析后出现反弹，可能是由于与周围组织重新平衡所致。第 1 天的平均未结合的血浆浓度-时间曲线下面积（0.415 L/h）与透析器血浆流量（约 20 L/h）相比无显著意义，给药剂量在透析液中回收的分数较小（剂量的 6.74%），个体间变异性较低（变异系数，14.7%）。因此，无论透析方案如何，都可以给予依罗达司他，并且无需在接受血液透析的终末期肾病患者中补充剂量。
