Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, China.
Hakata Clinic, Souseikai Global Clinical Research Center, Fukuoka, Japan.
Clin Pharmacokinet. 2024 Jun;63(6):901-915. doi: 10.1007/s40262-024-01387-y. Epub 2024 Jun 21.
Afferent neuronal hypersensitization via P2X3 receptor signaling has been implicated as a driver of several disorders, including refractory chronic cough, endometriosis, diabetic neuropathic pain, and overactive bladder. Eliapixant, a selective P2X3 receptor antagonist, has been in clinical development for all four disorders.
This paper describes pharmacokinetic (PK) and safety data from two phase I studies of eliapixant in healthy Japanese and Chinese participants and compares those data within the two populations and with previous multiple dose data from Caucasian participants.
Two separate phase I, single-center, randomized, placebo-controlled studies were conducted with healthy male participants. The Japanese study was single-blind and the Chinese study was double-blind. Eliapixant was administered as an oral amorphous solid dispersion immediate-release tablet in strengths of 25 mg, 75 mg, and 150 mg. PK characteristics after a single dose (SD) and at steady state (multiple dose [MD], twice daily), adverse events (AEs), and tolerability were evaluated. A post hoc comparison of PK characteristics after SD of eliapixant in Japanese and Chinese participants, and after MD of eliapixant in Japanese, Chinese, and Caucasian participants, was performed.
Overall, 36/39 participants enrolled in the Japanese/Chinese studies, respectively (mean [standard deviation] age 25.4 [6.5] and 26.7 [5.0] years, respectively). After SD administration, maximum plasma concentration (C) was higher among Japanese than Chinese participants in the 25 mg and 75 mg dose groups, but comparable in the 150 mg dose group. The area under the concentration-time curve (AUC) was comparable between Japanese and Chinese participants in the 25 mg and 75 mg dose groups, but lower among Japanese participants in the 150 mg group. Half-lives after SD and MD administration were also comparable in Japanese and Chinese participants. The post hoc analysis included 26 Japanese, 30 Chinese, and 50 Caucasian participants. Comparable exposure (C and AUC[0-12]) was observed after MD administration of eliapixant in Chinese and/or Japanese compared with Caucasian participants (geometric mean inter-ethnic ratios close to 1). The trough plasma concentration after eliapixant 150 mg MD, which was assumed to be relevant to eliapixant efficacy, was comparable across all ethnicity groups. Most AEs reported in the Japanese (eliapixant 75 mg SD, n = 2; eliapixant 150 mg MD, n = 2) and Chinese participants (eliapixant 25 mg SD, n = 7; eliapixant 75 mg SD, n = 6; eliapixant 150 mg SD, n = 7; eliapixant 150 mg MD, n = 9; placebo SD, n = 5; placebo MD, n = 1) were of mild intensity. Higher incidences of AEs in the Chinese population were likely due to differing standards of AE reporting between investigators.
Eliapixant was well tolerated by Japanese and Chinese participants. The inter-ethnic evaluation demonstrated similar PK characteristics across Japanese, Chinese, and Caucasian participants.
ClinicalTrials.gov identifier numbers: NCT04265781 and NCT04802343.
嘌呤能 P2X3 受体信号转导导致传入神经元致敏，这被认为是多种疾病的驱动因素，包括难治性慢性咳嗽、子宫内膜异位症、糖尿病性神经痛和膀胱过度活动症。埃利亚皮克桑特（eliapixant）是一种选择性 P2X3 受体拮抗剂，目前正在对所有四种疾病进行临床开发。
本文描述了在健康的日本和中国参与者中进行的两项埃利亚皮克桑特的 I 期临床研究的药代动力学（PK）和安全性数据，并比较了这两个人群内的数据以及与之前来自白种人的多次剂量数据。
两项单独的 I 期、单中心、随机、安慰剂对照研究在健康男性参与者中进行。日本研究为单盲，中国研究为双盲。埃利亚皮克桑特以 25mg、75mg 和 150mg 口服无定形固体分散体速释片的形式给药。评估单次剂量（SD）和稳态（多次剂量[MD]，每日两次）后的 PK 特征、不良事件（AE）和耐受性。对日本和中国参与者单次 SD 后埃利亚皮克桑特的 PK 特征以及日本、中国和白种人参与者多次 MD 后埃利亚皮克桑特的 PK 特征进行了事后比较。
总体而言，分别有 36/39 名参与者入组日本/中国研究（分别为平均[标准差]年龄 25.4[6.5]和 26.7[5.0]岁）。SD 给药后，25mg 和 75mg 剂量组中日本参与者的最大血浆浓度（C）高于中国参与者，但 150mg 剂量组中则相当。25mg 和 75mg 剂量组中日本和中国参与者的 AUC（时间曲线下面积）相当，但 150mg 组中日本参与者的 AUC 较低。SD 和 MD 给药后的半衰期也在日本和中国参与者中相当。事后分析包括 26 名日本参与者、30 名中国参与者和 50 名白种人参与者。与白种人参与者相比，埃利亚皮克桑特 MD 给药后在日本和/或中国参与者中观察到相当的暴露量（C 和 AUC[0-12]）（几何平均种间比值接近 1）。假设与埃利亚皮克桑特疗效相关的埃利亚皮克桑特 150mg MD 后的谷血浆浓度在所有种族群体中相当。日本（埃利亚皮克桑特 75mg SD，n=2；埃利亚皮克桑特 150mg MD，n=2）和中国参与者（埃利亚皮克桑特 25mg SD，n=7；埃利亚皮克桑特 75mg SD，n=6；埃利亚皮克桑特 150mg SD，n=7；埃利亚皮克桑特 150mg MD，n=9；安慰剂 SD，n=5；安慰剂 MD，n=1）中报告的大多数 AE 为轻度。中国人群中 AE 发生率较高可能是由于研究者之间 AE 报告标准不同。
埃利亚皮克桑特在日本和中国参与者中具有良好的耐受性。种族间评估表明，日本、中国和白种人参与者具有相似的 PK 特征。
ClinicalTrials.gov 标识符编号：NCT04265781 和 NCT04802343。
