Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring

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.

Figure 1

The coagulation cascade and targets of anticoagulant agents. LMWH, low molecular weight heparin; TF, tissue factor; UFH, unfractionated heparin; VKA, vitamin K antagonist [9].

Figure 2

Simulations of rivaroxaban plasma concentration–time profiles in typical patients compared with overall population estimates. Typical patients are elderly (90 years), have moderate to severe renal impairment; CrCl 30 ml/min), have low body weight (40 kg), or are elderly with low body weight. Patients receiving rivaroxaban 10 mg once daily (mean with 90% interval) [11]. CrCL/CrCl, creatinine clearance. Reproduced with permission from Mueck W, Borris LC, Dahl OE et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost 2008;100:453–461.

Figure 3

Predicted plasma rivaroxaban concentration–time profiles for extremes in age, renal function and body weight. Patients receiving rivaroxaban 20 mg once daily. The simulated patients had typical mean characteristics (age 60 years, body weight 80 kg, CrCl 90 ml/min) unless specified otherwise [12]. CL_CR/CrCl, creatinine clearance. Reproduced from Mueck W, Lensing AW, Agnelli G et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50:675–686 with permission from Adis (© Springer International Publishing AG 2011. All rights reserved).

Figure 4

Simulated venous thromboembolism treatment dosing regimen of rivaroxaban. Regimen is 15 mg bid for 3 weeks followed by 20 mg od (n=870) [12]. bid, twice daily; od, once daily. Reproduced from Mueck W, Lensing AW, Agnelli G et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50:675–686 with permission from Adis (© Springer International Publishing AG 2011. All rights reserved).