Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123, Allschwil, Switzerland.
CEPHA s.r.o, Komenského 19, 323 00, Pilsen, Czech Republic.
Clin Drug Investig. 2019 Nov;39(11):1117-1123. doi: 10.1007/s40261-019-00837-x.
The orally active dual endothelin receptor antagonist aprocitentan targets a novel pathway in the treatment of hypertension and could be a key player in the treatment of salt/volume-dependent hypertension. Its pharmacokinetic profile supports a once-daily dosing strategy.
As hypertensive patients may also experience concomitant renal disease, the objectives of this study were to evaluate the pharmacokinetics and tolerability of aprocitentan in subjects with severe renal function impairment (SRFI) and compare these with matched healthy subjects.
DESIGN, SETTING, PARTICIPANTS: In this open-label, single-center, phase 1 study (NCT03165071) eight subjects with SRFI (mean estimated glomerular filtration rate [eGFR] 21.9 mL/min/1.73 m) and eight healthy subjects (mean eGFR 94.9 mL/min/1.73 m) received a single dose of 50 mg of aprocitentan followed by an observation period of up to 17 days. Plasma pharmacokinetic parameters of aprocitentan were derived by noncompartmental analysis of the plasma concentration-time profiles. Differences in pharmacokinetic parameters were explored using geometric means ratio (GMR) and 90% confidence intervals (CIs) with SRFI subjects as test group and healthy subjects as reference group. Safety and tolerability evaluations included adverse events (AEs), electrocardiograms, vital signs, and clinical laboratory tests.
All 16 subjects received aprocitentan and completed the study. The pharmacokinetics of aprocitentan were similar in SRFI and healthy subjects with maximum plasma concentrations reached at 7.6 h and 5.0 h, respectively. Maximum plasma concentrations did not differ as indicated by a GMR (90% CI) of 1.04 (0.85-1.28). Due to a slightly lower observed clearance in SRFI subjects, half-life was longer (53.2 h compared to 47.4 h in healthy subjects), while exposure expressed as area under the curve was 34% higher (GMR 90% CI 1.13-1.58). There were no differences in plasma protein binding (> 99% bound). Aprocitentan was well tolerated in subjects with SRFI with no notable difference compared to healthy subjects.
Based on these single-dose results, subjects with mild, moderate, or severe renal function can be included in clinical studies without the need for dose adjustment.
口服双重内皮素受体拮抗剂阿普西坦能靶向治疗高血压的新途径，可能成为治疗盐/容量依赖性高血压的关键药物。其药代动力学特征支持每日一次的给药方案。
由于高血压患者也可能同时患有肾脏疾病，因此本研究的目的是评估严重肾功能损害（SRFI）患者中阿普西坦的药代动力学和耐受性，并将其与匹配的健康受试者进行比较。
设计、地点、参与者：在这项开放标签、单中心、I 期研究（NCT03165071）中，8 名 SRFI 患者（平均估计肾小球滤过率[eGFR]为 21.9 mL/min/1.73 m ）和 8 名健康受试者（平均 eGFR 为 94.9 mL/min/1.73 m ）接受了单次 50 mg 阿普西坦治疗，随后进行了长达 17 天的观察期。通过非房室分析血浆浓度-时间曲线，得出阿普西坦的药代动力学参数。采用几何均数比（GMR）和 90%置信区间（CI）比较试验组 SRFI 患者和对照组健康受试者的药代动力学参数。安全性和耐受性评估包括不良事件（AE）、心电图、生命体征和临床实验室检查。
所有 16 名受试者均接受了阿普西坦治疗，并完成了研究。阿普西坦在 SRFI 和健康受试者中的药代动力学相似，最大血浆浓度分别在 7.6 小时和 5.0 小时达到。最大血浆浓度没有差异，GMR（90%CI）为 1.04（0.85-1.28）。由于 SRFI 患者的观察清除率略低，半衰期较长（53.2 小时比健康受试者的 47.4 小时），而 AUC 表示的暴露量则高出 34%（GMR 90%CI 1.13-1.58）。血浆蛋白结合率无差异（>99%结合）。阿普西坦在 SRFI 患者中耐受性良好，与健康受试者相比无明显差异。
基于这些单次剂量结果，轻度、中度或重度肾功能损害的患者可以纳入临床试验，无需调整剂量。
