Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Clinical Science Division, CSPC Pharmaceutical Group Co., Ltd., Shijiazhuang, China.
Clin Transl Sci. 2023 Mar;16(3):447-458. doi: 10.1111/cts.13455. Epub 2022 Dec 9.
CSPCHA115 is a highly selective and potent antagonist of chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2). This study aimed to evaluate the pharmacokinetics (PKs), safety, and tolerability of single and multiple ascending doses of CSPCHA115 in Chinese healthy subjects. Two phase I studies both adopted a randomized, double-blind, placebo-controlled, single-center, and ascending-dose design. In the single ascending dose (SAD) study, subjects were randomly allocated to receive a single dose of CSPCHA115 (25-1000 mg) or a placebo. In the multiple ascending dose (MAD) study, 100, 200, 400, or 600 mg of CSPCHA115 or placebo were given to subjects once daily for 7 days. PK parameters were estimated by noncompartmental analysis. Safety was assessed by monitoring treatment-emergent adverse events (TEAEs), clinical laboratory tests, electrocardiograms, vital signs, and physical examinations throughout the study period. Forty-eight healthy subjects were enrolled in the SAD study, and 40 healthy subjects were in the MAD study. Following single and multiple administrations, CSPCHA115 was rapidly absorbed with a median time to maximum concentration of ~0.5-3.5 h; and the systemic exposure of CSPCHA115 generally increased dose-proportionally within the dose range studied. Steady-state was approximately achieved by day 5, and <1.5-fold accumulation was observed following multiple doses. Mean terminal half-life was ~8.16-16.43 h after a single dose. CSPCHA115 was well-tolerated in both studies, with a low overall incidence of TEAEs. The most common TEAE related to CSPCHA115 was hypertriglyceridemia. No significant safety concerns were identified in healthy subjects.
CSPCHA115 是一种高选择性和有效的趋化因子受体同源分子表达在 TH2 细胞上的拮抗剂 (CRTH2)。本研究旨在评估 CSPCHA115 在健康中国受试者中的单剂量和多剂量递增的药代动力学（PKs）、安全性和耐受性。两项 I 期研究均采用随机、双盲、安慰剂对照、单中心和递增剂量设计。在单剂量递增（SAD）研究中，受试者随机分配接受单剂量 CSPCHA115（25-1000mg）或安慰剂。在多剂量递增（MAD）研究中，100、200、400 或 600mg 的 CSPCHA115 或安慰剂每天一次给予受试者，连续给药 7 天。PK 参数通过非房室分析估算。通过监测整个研究期间的治疗后不良事件（TEAEs）、临床实验室检查、心电图、生命体征和体格检查来评估安全性。48 名健康受试者被纳入 SAD 研究，40 名健康受试者被纳入 MAD 研究。单次和多次给药后，CSPCHA115 迅速吸收，中位达峰时间约为 0.5-3.5 小时；在研究剂量范围内，CSPCHA115 的全身暴露通常呈剂量比例增加。在第 5 天达到稳态，多次给药后观察到<1.5 倍的蓄积。单次给药后平均终末半衰期约为 8.16-16.43 小时。在两项研究中，CSPCHA115 均具有良好的耐受性，总不良反应发生率较低。与 CSPCHA115 相关的最常见的不良反应是高甘油三酯血症。在健康受试者中未发现明显的安全性问题。
