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

• Published in: European journal of pharmaceutical sciences Vol. 185; p. 106437
• Main Authors: Chen, Wenjun, Ruan, Zourong, Lou, Honggang, Wang, Lu, Shao, Rong, Li, Fenghua, Jiang, Bo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2023
• Subjects: Area Under Curve; Asian People; CX3002; Dose-Response Relationship, Drug; Double-Blind Method; East Asian People; Exposure-response; Factor Xa Inhibitors; Healthy subjects; Healthy Volunteers; Humans; Pharmacokinetics; Safety; CX3002; Exposure-response; Healthy subjects; Safety; Pharmacokinetics
• ISSN: 0928-0987; 1879-0720; 1879-0720
• DOI: 10.1016/j.ejps.2023.106437

•CX3002 is a novel inhibitor of factor Xa. Model-informed approach was used to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of CX3002 in a randomized ascending-dose study in Chinese healthy subjects.•CX3002 exhibited satisfactory safety and tolerability in healthy subjects. Cmax and AUC of CX3002 increased with dose from 1.0 to 30 mg, but less-than-proportional increases were observed. Anti-xa activity showed dose-related increases after administration of CX3002.•The PK of CX3002 were predictable, and correlated with PD effects. This study supported further clinical evaluation of CX3002. 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. 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 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. A 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. 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. [Display omitted]