Effects of Verapamil and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban

Concomitant use of rivaroxaban with non-dihydropyridine calcium channel blockers (non-DHPs) might lead to an increase of systemic rivaroxaban exposure and anticoagulant effects in relation to the inhibition of metabolic enzymes and/or transporters by non-DHPs. This study was designed to evaluate the effects of verapamil and diltiazem on the pharmacokinetics and the prolongation of prothrombin time of rivaroxaban in rats. The data were analyzed using a pharmacokinetic/pharmacodynamics (PK/PD) modeling approach to quantify the influence of verapamil. Verapamil increased the systemic exposure of rivaroxaban by 2.8-fold (p <0.001) which was probably due to the inhibition of efflux transportation rather than metabolism. Prothrombin time was also prolonged in a proportional manner; diltiazem did not show any significant effects, however. A transit PK model in the absorption process comprehensively describes the double-peaks of rivaroxaban plasma concentrations and the corresponding change of prothrombin time with a simple linear relationship. The slope of prothrombin time vs. rivaroxaban plasma concentration in rats was retrospectively found to be insensitive by about 5.4-fold compared to than in humans. More than a 67% dose reduction in rivaroxaban is suggested in terms of both a pharmacokinetic point of view, and the sensitivity differences on the prolongation of prothrombin time when used concomitantly with verapamil.

Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the therapeutic monitoring of patients treated with rivaroxaban

SummaryPossibilities to monitor rivaroxaban therapy could be useful in certain circumstances. Prothrombin time (PT) or chromogenic anti-Xa assays such as the Biophen Direct Factor Xa Inhibitor® (DiXaI) have been proposed to estimate rivaroxaban concentrations but are mainly based on in vitro studies. The study aim was to compare PT and Biophen DiXaI® measurements with liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurements in plasma samples from patients treated with Xarelto®. Fifty-two plasma samples were included. PT was performed using Innovin® and Triniclot PT Excel S®. Biophen DiXaI® was performed according to instructions from the manufacturer. The rivaroxaban plasma concentration ranged between 0 and 485 ng/ml as measured by LC-MS/MS. The limits of quantification were 30 ng/ml and 5 ng/ml for Biophen DiXaI® and LC-MS/MS, respectively. The linear correlation between Biophen DiXaI® and LC-MS/ MS analyses was high for all rivaroxaban concentrations (r2 = 0.95). For concentrations ≤100 ng/ml, r2-value was 0.83. The Bland-Altman analysis showed a mean difference of −16 ng/ml (SD: 25 ng/ml). The PT methods did not correlate well with plasma concentrations measured by LC-MS/MS (r2 ≈ 0.60). In conclusion, the important interindividual variability and the poor correlation with LC-MS/MS preclude the use of PT to estimate rivaroxaban concentrations. Thanks to its small inter-individual variability and good agreement with LC-MS/ MS measurements, we recommend the use of Biophen DiXaI® assays to estimate concentrations of rivaroxaban >30 ng/ml. Quantification of low rivaroxaban levels (<30 ng/ml) requires the LC-MS/MS method.