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Drug Metab Pharmacokinet. 2018 Aug;33(4):188-193. doi: 10.1016/j.dmpk.2018.02.002. Epub 2018 Mar 15.

An analysis on distribution and inter-relationships of biomarkers under rivaroxaban in Japanese patients with non-valvular atrial fibrillation (CVI ARO 1).

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Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan. Electronic address:
Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan.
Certara, Tokyo, Japan.


Prothrombin time (PT) has been widely used for measuring anticoagulation intensity under rivaroxaban therapy, but precise information has not been well established yet. Consecutive 96 non-valvular atrial fibrillation (NVAF) under rivaroxaban between Jan/June, 2015 were recruited. Serum concentration (SC) and PT with 5 representative reagents available in Japan (Neoplastin Plus®, Thromborel S®, Thrombocheck PT®, Thrombocheck PT Plus®, and Recombiplastin®) at 2-4 hours after (peak) and before intake of rivaroxaban (trough) were measured at outpatient clinic in the cardiovascular institute (CVI ARO study 1). Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. An oral one-compartment model was employed to describe the population pharmacokinetics of rivaroxaban. The pharmacokinetics of rivaroxaban were affected by creatinine clearance, alanine aminotransferase, and use of CYP3A4 or P-gp inhibitors. PTs with 5 reagents were predicted by pharmacodinamic models with SC, hematocrit, serum albumin, and age, with medium predicting ability (highest/lowest R2 = 0.746/0.658 in Recombiplastin/Thromborel S, respectively). This population analysis in NVAF patients under rivaroxaban therapy demonstrated that pharmacokinetics of rivaroxaban was described by an oral one-compartment model with expected covariates, and can be assessed by PT with available reagents in Japan with medium predicting ability.


Anticoagulation; Atrial fibrillation; Population pharmacokinetics; Prothrombin time; Rivaroxaban; Serum concentration

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