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

Abstract

BackgroundAutotaxin (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. MethodsA 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. ResultsA 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 (Tmax) of 1.75, 2.75 and 3.5 h, respectively and eliminated with mean elimination half-life (t1/2) of 8.77, 10.58 and 10.57 h, respectively. Peak concentration (Cmax), plasma area under concentration–time curve from time 0 to the last measurable concentration (AUC0-t) and to infinity (AUC0-∞) increased in dose-proportional manner for 100 mg to 400 mg FTP-198. Food intake slightly increased the Cmax, AUC0-t and AUC0-∞ and prolonged Tmax, but not affecting t1/2 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. ConclusionPharmacokinetics, pharmacodynamics, safety and tolerability of FTP-198 support further subsequent clinical development of FTP -198 in IPF patients.