新型、选择性 Autotaxin 抑制剂 FTP-198 在健康受试者中的药代动力学、药效学、安全性和耐受性：一项 I 期随机安慰剂对照试验。
Pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198, a novel, selective Autotaxin inhibitor, in healthy subjects: A phase I randomized placebo-controlled trial.
机构信息
Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu, Sichuan, 610044, China; Clinical Trial Center, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu, Sichuan, 610044, China.
Clinical Trial Center, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu, Sichuan, 610044, China.
出版信息
Eur J Pharm Sci. 2023 Oct 1;189:106552. doi: 10.1016/j.ejps.2023.106552. Epub 2023 Jul 31.
BACKGROUND
Autotaxin (ATX) and lysophosphatidic acid (LPA) play an important role in pathogenesis of idiopathic pulmonary fibrosis (IPF). FTP-198 is an oral, novel and selective ATX inhibitor indicated for treating IPF. The study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 in healthy subjects.
METHODS
A single-center, randomized, double-blind, placebo-controlled, single ascending-dose Phase I study was performed. Pharmacokinetics, pharmacodynamics, food effect on pharmacokinetics, elimination, safety and tolerability of FTP-198 were evaluated.
RESULTS
A total of 30 subjects were enrolled and completed the study. After oral administration of single ascending-dose of 100 mg, 300 mg and 400 mg FTP-198 under fasted condition, FTP-198 was absorbed with median time to reach peak concentration (T) of 1.75, 2.75 and 3.5 h, respectively and eliminated with mean elimination half-life (t) of 8.77, 10.58 and 10.57 h, respectively. Peak concentration (C), plasma area under concentration-time curve from time 0 to the last measurable concentration (AUC) and to infinity (AUC) increased in dose-proportional manner for 100 mg to 400 mg FTP-198. Food intake slightly increased the C, AUC and AUC and prolonged T, but not affecting t of FTP-198 compared with fasted state. The pharmacodynamic biomarker plasma lysophosphatidic acid (LPA) 18:2 decreased significantly for 100 mg to 400 mg FTP-198, with inhibition rate from baseline reaching approximately 80% at 24 h post dosing, and higher dose of FTP-198 increased the time to maintain inhibitory plateau. FTP-198 was eliminated from the body almost with no unchanged drug excreted in urine and a small amount of unchanged drug detected in feces of human. Moreover, FTP-198 exhibited favorable safety and tolerability in healthy subjects.
CONCLUSION
Pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 support further subsequent clinical development of FTP -198 in IPF patients.
背景
自分泌酶（ATX）和溶血磷脂酸（LPA）在特发性肺纤维化（IPF）的发病机制中起着重要作用。FTP-198 是一种新型、口服、选择性 ATX 抑制剂，用于治疗 IPF。本研究旨在评估 FTP-198 在健康受试者中的药代动力学、药效学、安全性和耐受性。
方法
进行了一项单中心、随机、双盲、安慰剂对照、单次递增剂量的 I 期研究。评估了 FTP-198 的药代动力学、药效学、食物对药代动力学的影响、消除、安全性和耐受性。
结果
共纳入 30 名受试者完成了研究。在禁食条件下单次口服 100mg、300mg 和 400mg 的 FTP-198 后，FTP-198 的中位达峰时间（T）分别为 1.75、2.75 和 3.5h，平均消除半衰期（t）分别为 8.77、10.58 和 10.57h。100mg 至 400mg FTP-198 的峰浓度（C）、从 0 到最后可测量浓度的时间（AUC）和无穷大（AUC）的血浆浓度-时间曲线下面积呈剂量比例增加。与禁食状态相比，食物摄入略微增加了 C、AUC 和 AUC，并延长了 T，但不影响 FTP-198 的 t。药效学生物标志物血浆溶血磷脂酸（LPA）18:2 对 100mg 至 400mg FTP-198 显著降低，在给药后 24h 时从基线抑制率达到约 80%，高剂量的 FTP-198 增加了维持抑制平台的时间。FTP-198 从体内几乎没有以原形药物排泄，少量原形药物在人粪便中被检测到。此外，FTP-198 在健康受试者中表现出良好的安全性和耐受性。
结论
FTP-198 的药代动力学、药效学、安全性和耐受性支持其在 IPF 患者中进一步的后续临床开发。
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