Sidharta Patricia N, Diamant Zuzana, Dingemanse Jasper
Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123, Allschwil, Switzerland.
Fundam Clin Pharmacol. 2014 Dec;28(6):690-9. doi: 10.1111/fcp.12079. Epub 2014 May 11.
Chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single- and multiple-dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double-blind, placebo-controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one-dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single- and multiple-dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single- and multiple-dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2-3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry-into-human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders.
辅助性T细胞2（Th2）细胞上表达的趋化因子受体同源分子（CRTH2）是前列腺素D2（PGD2）的G蛋白偶联受体，PGD2是哮喘和过敏性鼻炎等炎症性疾病的关键介质。在本研究中，我们调查了口服活性、强效且选择性的CRTH2拮抗剂司替哌兰特的单剂量和多剂量耐受性及药代动力学（PKs）。这项随机、双盲、安慰剂对照研究在健康男性受试者中分为两个部分进行。在研究A部分，将高达2000 mg的司替哌兰特单剂量口服给药或给予安慰剂，每组8名受试者，依次进行。此外，在一个剂量组中研究了食物对PKs的影响。在研究B部分，两组受试者在5.5天内每日两次接受500或1000 mg司替哌兰特或安慰剂。定期测定耐受性变量以及司替哌兰特的血浆和尿液水平。司替哌兰特在单剂量和多剂量给药后耐受性良好。头痛是最常报告的不良事件。未观察到对耐受性变量的治疗效果。单剂量和多剂量给药后，司替哌兰特迅速吸收，呈现双相消除模式，消除半衰期在10至18小时之间。2至3天后达到稳态，司替哌兰特未蓄积。食物存在时司替哌兰特的暴露量较低。未改变的司替哌兰特的尿排泄量不超过给药剂量的7%。在这项人体首次研究中，司替哌兰特显示出良好的耐受性和有利的PK特征，因此有理由对其进行炎症性疾病治疗方面的开发。
