Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes

Abstract

AIMS : The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS : A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. RESULTS : The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h-1 (interindividual variability, 139%), 6.48 l h-1 (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. CONCLUSIONS : The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposureprothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied

Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease

“…Rivaroxaban is an effective and well-characterised anticoagulant (14)(15)(16)(17)(18)(19)(20). The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied (16,17,20).…”

“…The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied (16,17,20). Rivaroxaban is absorbed rapidly, with maximum concentrations (C max ) appearing 2-4 h after single tablet intake, and maximal factor Xa inhibition seen after 1-4 h (14, 18).…”

“…Rivaroxaban is absorbed rapidly, with maximum concentrations (C max ) appearing 2-4 h after single tablet intake, and maximal factor Xa inhibition seen after 1-4 h (14, 18). At total daily oral doses of rivaroxaban of 5-60 mg , C max ranges (mean values) from 40 µg/l to 400 µg/l, and minimum plasma concentration (C trough ) (mean values) from 8 µg/l to 160 µg/l (16,17,19,20).…”

Prevention and Treatment of Venous Thromboembolism and Pulmonary Embolism: The Role of Novel Oral Anticoagulants

“…Thus, phase II and phase III studies have been completed in patients subjected to orthopedic surgery and the available results have shown a very hopeful perspective for its use not only in patients for prophylaxis against VTE, but also in patients being at high risk of thrombosis [120,121]. Rivaroxaban has been shown to be superior to dalteparin in terms of inhibiting thrombin generation in the first 24 hours after total hip replacement or total knee replacement surgery [122].…”

“…Food has also no obvious effect on plasma concentrations of rivaroxaban. PT, aPTT and INR are not useful indicators of rivaroxaban activity since the results should be interpreted be on the basis of the clotting assays used [115,120].…”