Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

Abstract

Background Rivaroxaban is a direct factor Xa inhibitor with substantial inter‐individual pharmacokinetic (PK) variability. Pharmacodynamic (PD) variability, especially assessed with thrombin generation (TG), has been less documented. Objectives (i) To assess TG parameter time profiles in healthy volunteers, with TG being studied under different conditions and (ii) to model the relationship between rivaroxaban concentrations and TG parameters and subsequently estimate interindividual variability. Methods Sixty healthy male volunteers (DRIVING‐NCT01627665) received a single 40‐mg rivaroxaban dose. Blood sampling was performed at baseline and 10 predefined time points over 24 h. The TG was investigated with the fully automated ST‐Genesia system (Stago), using two tissue‐factor (TF) concentrations, in the absence (−), or presence (+) of thrombomodulin (TM) for the lowest one. The PD models were built to characterize the relationships between plasma rivaroxaban concentrations and endogenous thrombin potential (ETP) or peak height induced by the lowest TF concentration. Results Thrombin generation parameter time profiles with the lowest TF concentration showed a good sensitivity to rivaroxaban, especially +TM (active protein C negative feedback). The relationship between rivaroxaban concentrations and TG parameters was modeled with a sigmoidal relation. Mean rivaroxaban concentrations halving the baseline value of ETP and peak height (−TM) (C50) were of 284 and 33.2 ng/mL, respectively: +TM, C50 declined to 19.4 and 13.8 ng/mL, reflecting a powerful inhibitory effect. The estimated C50 population coefficients of variation were of 12.2% (−TM) and 31.3% (+TM) with the peak height models, 34.8% (+TM) with the ETP model. Conclusions This low‐rivaroxaban to moderate‐rivaroxaban PD variability in healthy volunteers contrasts with the substantial PK variability and deserves to be studied in different patient settings.

Direct oral anticoagulant plasma levels and thrombin generation on ST Genesia system

“…In that study, DOAC treatment led to a decrease in ETP that was less pronounced than the inhibition of peak thrombin. The same effect was shown with ST Genesia and the STG‐DrugScreen reagent in 17 healthy volunteers after a single dose of 40 mg rivaroxaban 13 . Another study on 10 healthy male volunteers after a single dose of dabigatran, rivaroxaban, and apixaban using the CAT system revealed a high correlation for lag time, peak thrombin, TTP, and velocity index with apixaban and rivaroxaban drug levels, while the highest correlation for dabigatran was found with lag time and to a lesser extent with TTP.…”

“…STG‐DrugScreen contains a mixture of phospholipids, recombinant tissue factor (TF) at a relatively high picomolar concentration and uses human thrombin in buffer for calibration. Detailed information about TG measurement with ST Genesia have been previously described 11,13 …”

Inhibition of thrombin generation 12 hours after intake of direct oral anticoagulants

“…TG measurements of all patients and controls were performed using the ST‐Genesia Thrombin Generation System (Diagnostica Stago) with the reagent STG‐DrugScreen 10 according to manufacturer's instructions. The measurement principle is similar to the semiautomated calibrated automated thrombogram (CAT) 11 with differences in temperature control and calibration 12 . The ST Genesia uses dedicated reagents, calibrators, reference plasmas, and quality controls.…”

“…STG‐DrugScreen contains a mixture of phospholipids and recombinant transferrin at a relatively high picomolar concentration and uses human thrombin in buffer for calibration. Detailed information has been previously described 10,12 . The following parameters were measured: lag time, peak thrombin, time to peak, endogenous thrombin potential (ETP), and velocity index.…”

Contrasting Role of Concentration in Rivaroxaban Induced Toxicity and Oxidative Stress in Isolated Kidney Mitochondria

“…This study was designed to investigate the effects of rivaroxaban on oxidative stress and mitochondrial toxicity in isolated rat kidney mitochondria. Rivaroxaban is known to be an inhibitor of factor Xa [26,27]. This drug has a high bioavailability and rapid absorption [11,13].…”