Clinical Sciences, Clinical Pharmacology Cardiovascular/Hematology, Global Drug Discovery, Bayer AG, Wuppertal, Germany.
Research and Clinical Science Statistics, Clinical Pharmacology Cardiovascular/Hematology, Global Drug Discovery, Bayer AG, Berlin, Germany.
Br J Clin Pharmacol. 2018 Jul;84(7):1557-1565. doi: 10.1111/bcp.13584. Epub 2018 May 14.
Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers.
This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution.
In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters.
Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.
促红细胞生成素（EPO）合成不足是慢性肾脏病患者肾性贫血的一个相关原因。莫立司他是一种选择性低氧诱导因子脯氨酰羟化酶（HIF-PH）抑制剂，在临床前模型中可剂量依赖性地增加内源性 EPO 水平。我们研究了健康男性志愿者单次口服莫立司他的药代动力学、安全性、耐受性和对 EPO 水平的影响。
这是一项单中心、随机、单盲、安慰剂对照、组间比较、剂量递增研究。莫立司他以聚乙二醇为基础的溶液形式给予 5、12.5、25、37.5 或 50mg 的剂量。
共有 45 名志愿者接受了莫立司他治疗，14 名志愿者接受了安慰剂治疗。莫立司他吸收迅速，平均最大血浆浓度和浓度-时间曲线下面积呈剂量依赖性增加。平均终末半衰期为 4.64-10.40 小时。单次口服莫立司他 12.5mg 及以上剂量可观察到内源性 EPO 显著增加。接受安慰剂的志愿者的几何平均峰值 EPO 水平为 14.8IU/L（90%置信区间：13.0，16.9），而接受莫立司他 50mg 的志愿者的几何平均峰值 EPO 水平为 39.8IU/L（90%置信区间：29.4，53.8）。EPO 水平的时间过程与 EPO 的正常昼夜变化相似。最大 EPO 水平约在给药后 12 小时观察到，并在约 24-48 小时后恢复到基线。莫立司他的所有剂量均耐受良好，生命体征或实验室安全参数无显著变化。
健康志愿者口服莫立司他可引起内源性 EPO 的剂量依赖性增加。这些结果支持莫立司他作为治疗肾性贫血患者的一种新的潜在治疗方法的持续开发。
