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

Background and objective: CX3002 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.Methods: The 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 pharma- codynamics (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.Results: A total of 84 subjects were enrolled and all participants completed the study. CX3002 exhibited satis- factory 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.Conclusions: CX3002 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.