Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban

Abstract

Rivaroxaban is an oral, direct Factor Xa inhibitor that targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It is absorbed rapidly, with maximum plasma concentrations being reached 2-4 h after tablet intake. Oral bioavailability is high (80-100 %) for the 10 mg tablet irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. Variability in the pharmacokinetic parameters is moderate (coefficient of variation 30-40 %). The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5-9 h in healthy young subjects and 11-13 h in elderly subjects. Rivaroxaban produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for inhibition of Factor Xa activity can be described by an E max model, and prothrombin time prolongation by a linear model. Rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications. Rivaroxaban has been approved for clinical use in several thromboembolic disorders.

Fig. 1

Chemical structure of rivaroxaban [17]

Fig. 2

Summary of absorption, distribution, metabolism, and elimination of rivaroxaban [3, 16, 36]. All numbers given are approximate. BCRP breast cancer resistance protein, CL _sys systemic (plasma) clearance, CL _R renal clearance (via active secretion CL_RS and glomerular filtration CL_RF), CYP3A4 cytochrome P450 3A4, CYP2J2 cytochrome P450 2J2, F _abs absolute bioavailability, P-gp P-glycoprotein, V _ss volume of distribution at steady-state

Fig. 3

Predicted steady-state rivaroxaban plasma concentration–time profiles for typical patients with extremes in age, renal function (expressed as calculated CL_CR), and body weight, according to the relationships established in the pharmacokinetic model, for patients receiving rivaroxaban 20 mg once daily compared with the post hoc estimated rivaroxaban plasma concentration range [geometric mean, 5^th–95^th percentiles] of the 20 mg once-daily treatment group in the phase II EINSTEIN DVT study [15]. Reproduced from Mueck et al. [15] with permission from Springer International Publishing AG (© Adis Data Information BV 2011. All rights reserved.). CL _CR creatinine clearance

Fig. 4

Concentration–effect relationship for Factor Xa activity (a) and prothrombin time (b) in healthy male subjects receiving rivaroxaban [16]. Reproduced from Mueck et al. [16] with permission from Dustri-Verlag Dr. Karl Feistle © 2007