Population Pharmacokinetics And Pharmacodynamics Of Rivaroxaban In Patients With High Risk Of Thrombosis In China

Thromboembolism is a significant cause of morbidity and mortality. Anticoagulants are widely used in the prevention and treatment of thromboembolic disorders, such as acute coronary syndrome, deep vein thrombosis, and pulmonary embolism, etc. Tradi-tional anticoagulants have drawbacks since warfarin has numerous interactions with oth-er drugs and food and low molecular weight heparin has to be injected subcutaneously. These factors may be problematic in long-term use. Rivaroxaban, an oral direct inhibitor of factor Xa, is becoming more and more important in prevention and treatment of thromboembolic disorders with predictable pharmacokinetic and pharmacodynamic pro-files, little interaction with food or drugs. After completion of phase I, II and III clinical trials, rivaroxaban has been approved to be on market by China’s state Food and Drug Administration. Different dosing regimens were recommended for different types of dis-eases and it is not clear whether individualized dosing strategy is needed in Chinese pa-tients for better efficacy and safety in our clinical practice. The aim of this analysis was to define the pharmacokinetics and pharmacodynamics of rivaroxaban in Chinese pa-tients undergoing major orthopedic surgery or with venous thrombosis by identifying population pharmacokinetics and pharmacodynamics models of rivaroxaban. The article was divided into three parts, study methods and results for each part were as follows.Part I:A sensitive and accurate UPLC-MS/MS method was developed and validated for the quantification of rivaroxaban. This method was validated with respect of linearity, selectivity, precision, recovery and stability, etc. The validation results indicated that this method is convenient, sensitive and accurate which was suitable for the assay of riva-roxaban in the subsequent pharmacokinetic study.Part II:Spare blood samples were taken from all patients participating in this study (n=151). Demographic data and clinical data were described, while rivaroxaban plasma concentration, prothrombin time and activated partial thromboplastin time were deter-mined. The results implied that there were differences between health subjects and pa-tients in the perspective of pharmacokinetics and pharmacodynamics of rivaroxaban. Further studies should be performed to explore the possible physiological or pathological factors that contributed to the differences.Part III:Population pharmacokinetic and pharmacodynamic model of rivaroxaban was developed using non-linear mixed effect modeling. An oral two-compartment model described the population pharmacokinetics of rivaroxaban well.. The pharmacokinetics of rivaroxaban was affected by an expected covariant:CLcr. The population pharmacody-namics of rivaroxaban in patients was found to be affected by surgery.Above all, a population pharmacokinetic and pharmacodynamic model in Chinese patients was built with providing evidence for individualized dosing strategy in China’s clinical practice.