Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and
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REVIEW
Open Access
Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring Wolfgang Mueck*, Stephan Schwers and Jan Stampfuss
Abstract Unlike traditional anticoagulants, the more recently developed agents rivaroxaban, dabigatran and apixaban target specific factors in the coagulation cascade to attenuate thrombosis. Rivaroxaban and apixaban directly inhibit Factor Xa, whereas dabigatran directly inhibits thrombin. All three drugs exhibit predictable pharmacokinetic and pharmacodynamic characteristics that allow for fixed oral doses in a variety of settings. The population pharmacokinetics of rivaroxaban, and also dabigatran, have been evaluated in a series of models using patient data from phase II and III clinical studies. These models point towards a consistent pharmacokinetic and pharmacodynamic profile, even when extreme demographic factors are taken into account, meaning that doses rarely need to be adjusted. The exception is in certain patients with renal impairment, for whom pharmacokinetic modelling provided the rationale for reduced doses as part of some regimens. Although not routinely required, the ability to measure plasma concentrations of these agents could be advantageous in emergency situations, such as overdose. Specific pharmacokinetic and pharmacodynamic characteristics must be taken into account when selecting an appropriate assay for monitoring. The anti-Factor Xa chromogenic assays now available are likely to provide the most appropriate means of determining plasma concentrations of rivaroxaban and apixaban, and specific assays for dabigatran are in development. Keywords: Rivaroxaban, Population Pharmacokinetics, Dabigatran, Apixaban, Coagulation Monitoring
Introduction In recent years, the scope for effective management of venous and arterial thromboembolic diseases has been enhanced by the advent of novel oral anticoagulants (OACs) that, unlike traditional oral vitamin K antagonists (VKAs) [1], are given at fixed doses and have a lower potential for drug and food interactions [2]. These agents show similar or improved efficacy and safety profiles compared with VKAs, such as warfarin, and established parenteral agents, including unfractionated heparin and low molecular weight heparin [2]. The currently licensed novel OACs are rivaroxaban (XareltoW, Bayer Pharma AG and Janssen Pharmaceuticals, Inc.), dabigatran (PradaxaW, Boehringer Ingelheim * Correspondence: [email protected] Bayer Pharma AG, Clinical Pharmacology, D-42096 Wuppertal, Germany
International GmbH) and apixaban (EliquisW, BristolMyers Squibb and Pfizer EEIG). All three of these agents, and others in development, are under investigation for the management of multiple thromboembolic disorders. Rivaroxaban, a direct Factor Xa inhibitor, is now approved in the European Union (EU), United States (US) and elsewhere for the prevention of venous thromboembolism (VTE) in adults who have undergone elective hip or knee replacemen
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