Pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198, a novel, selective Autotaxin inhibitor, in healthy subjects: A phase I randomized placebo-controlled trial

Ling Yang; Pei Shu; Nan Wu; Mengyue Hu; Zhu Luo

doi:10.1016/j.ejps.2023.106552

Pharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198, a novel, selective Autotaxin inhibitor, in healthy subjects: A phase I randomized placebo-controlled trial

Eur J Pharm Sci. 2023 Oct 1:189:106552. doi: 10.1016/j.ejps.2023.106552. Epub 2023 Jul 31.

Authors

Ling Yang¹, Pei Shu², Nan Wu³, Mengyue Hu³, Zhu Luo⁴

Affiliations

¹ 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.
² Clinical Trial Center, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu, Sichuan, 610044, China.
³ Haisco Pharmaceutical Group Co., LtPd., Chengdu, China.
⁴ Clinical Trial Center, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu, Sichuan, 610044, China. Electronic address: luozhu720@163.com.

PMID: 37532064
DOI: 10.1016/j.ejps.2023.106552

Abstract

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_max) of 1.75, 2.75 and 3.5 h, respectively and eliminated with mean elimination half-life (t_1/2) of 8.77, 10.58 and 10.57 h, respectively. Peak concentration (C_max), plasma area under concentration-time curve from time 0 to the last measurable concentration (AUC_0-t) and to infinity (AUC_0-∞) increased in dose-proportional manner for 100 mg to 400 mg FTP-198. Food intake slightly increased the C_max, AUC_0-t and AUC_0-∞ and prolonged T_max, but not affecting t_1/2 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.

Keywords: Autotaxin inhibitor; Idiopathic pulmonary fibrosis; Pharmacodynamics; Pharmacokinetics; Phase i study; Safety.

Publication types

Randomized Controlled Trial
Clinical Trial, Phase I

MeSH terms

Administration, Oral
Area Under Curve
Dose-Response Relationship, Drug
Double-Blind Method
Half-Life
Healthy Volunteers
Humans
Idiopathic Pulmonary Fibrosis* / drug therapy