Safety, pharmacokinetics and exploratory exposure-response analysis of CX3002, a novel inhibitor of Xa, in Chinese healthy subjects

Abstract

Background and objectiveCX3002 is a structurally novel inhibitor of factor Xa, with promising prospects. This study aims to report the results of a first-in-human ascending-dose study of CX3002 in Chinese healthy subjects, and to establish an exploratory population pharmacokinetic/pharmacodynamic (PK/PD) model to investigate the exposure-response relationship of CX3002. MethodsThe randomized, double-blind, placebo-controlled study included six single-dose groups and three multiple-dose groups, with a dose range of 1–30 mg. Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of CX3002 were evaluated. PK of CX3002 was analyzed using both non-compartment method and population modeling. PK/PD model was developed using nonlinear mixed effect modeling approach and was evaluated by prediction-corrected visual predictive check and bootstrap methods. ResultsA total of 84 subjects were enrolled and all participants completed the study. CX3002 exhibited satisfactory safety and tolerability in healthy subjects. Cmax and AUC of CX3002 increased with dose from 1 to 30 mg, but less-than-proportional increases were observed. There was no obvious accumulation with multiple doses. Anti-Xa activity showed dose-related increases after administration of CX3002 but not placebo. The PK of CX3002 was well described by a two-compartment model with a modification of bioavailability according to dose, and anti-Xa activity was described by a Hill function. No covariate was identified significant based on the limited data in this study. ConclusionsCX3002 was well tolerated and resulted in dose-related anti-Xa activity across the dose range. The PK of CX3002 were predictable, and correlated with PD effects. Continued clinical investigation of CX3002 was supported. Chinadrugtrials.org.cn identifier: CTR20190153.