Rivaroxaban Plasma Concentrations Research Articles

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans.

To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban. Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract. The geometric mean ratios for the area under the concentration-time curve and Cmax of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding Tmax (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping. The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban.

A prospective observational study of the rapid detection of clinically-relevant plasma direct oral anticoagulant levels following acute traumatic injury.

In urgent clinical situations, such as trauma, urgent surgery or before thrombolysis, rapid quantification of direct oral anticoagulant plasma drug levels is warranted. Using the ClotPro® analyser, we assessed two novel viscoelastic tests for detection of clinically-relevant plasma drug levels in trauma patients. The ecarin clotting time was used to assess the plasma concentration of dabigatran and Russell´s viper venom clotting time to determine the plasma concentration of direct factor Xa inhibitors. In parallel, plasma concentrations were analysed using plasma-based chromogenic assays. A total of 203 simultaneous measurements were performed.Strong to very strong linear correlations were detected between ecarin clotting time and plasma concentration of dabigatran (r=0.9693), and between Russell´s viper venom clotting time and plasma concentrations of apixaban (r=0.7391), edoxaban (r=0.9251) and rivaroxaban (r=0.8792), all p<0.001. An ecarin clotting time≥189seconds provided 100% sensitivity and 90% specificity for detecting plasma dabigatran concentrations≥50ng.ml-1 . Corresponding Russell´s viper venom clotting time cut-off values were≥136seconds for apixaban (80% sensitivity, 88% specificity), ≥ 168seconds for edoxaban (100% sensitivity, 100% specificity) and≥177seconds for rivaroxaban (90% sensitivity, 100% specificity). Detection of drug levels≥100ng.ml-1 was also investigated: for dabigatran, an ecarin clotting time≥315seconds yielded 92% sensitivity and 100% specificity; while Russell´s viper venom clotting time cut-offs of 191, 188 and 196seconds were calculated for apixaban (67% sensitivity, 88% specificity), edoxaban (100% sensitivity, 75% specificity) and rivaroxaban (100% sensitivity, 91% specificity), respectively. We have demonstrated strong positive correlations between plasma drug levels and clotting time values in the specific ClotPro assays. Cut-off values for detecting clinically-relevant drug levels showed high levels of sensitivity and specificity.

Drug-drug interaction of rivaroxaban and calcium channel blockers in patients aged 80 years and older with nonvalvular atrial fibrillation.

Objectives For revealing the peculiarities of the drug-drug interaction of rivaroxaban (substrate CYP3A4 and P-gp) and calcium channel blockers (CCBs) (verapamil- inhibitor CYP3A4 and P-gp and amlodipine- substrate CYP3A4) in patients 80 years and older with nonvalvular atrial fibrillation (NAF) we studied 128 patients. Methods All patients were divided into groups depending on the therapy taken: the 1st- rivaroxaban+ amlodipine (n=51), the 2nd- rivaroxaban+ verapamil (n=30), the control group- rivaroxaban without CCBs (n=47). A trough steady-state plasma concentration (C min,ss) of rivaroxaban, prothrombin time (PT) in the blood plasma and the event of clinically relevant non-major (CRNM) bleeding were assessed for each patient. Results Patient in group 2 had higher C min,ss of rivaroxaban, PT and CRNM than subjects in the control group (Me 73.8 [50.6-108.8] ng/mL vs. 40.5 [25.6-74.3] ng/mL; Me 14.8 [13.4-17.3] s vs. 13.8 [12.6-14.4] s; 34% vs. 13%, respectively, p<0.05 for all). When compared, the PT and complication rate in group 1 with the control group C min,ss of rivaroxaban were practically the same (p>0.05 for all). Conclusions In patients≥80 years with NAF, the use of rivaroxaban in combination with verapamil may not be safe and can lead to CRNM bleeding.

Drug-drug interaction of rivaroxaban and calcium channel blockers in patients aged 80 years and older with nonvalvular atrial fibrillation.

Objectives For revealing the peculiarities of the drug-drug interaction of rivaroxaban (substrate CYP3A4 and P-gp) and calcium channel blockers (CCBs) (verapamil- inhibitor CYP3A4 and P-gp and amlodipine- substrate CYP3A4) in patients 80 years and older with nonvalvular atrial fibrillation (NAF) we studied 128 patients. Methods All patients were divided into groups depending on the therapy taken: the 1st- rivaroxaban+ amlodipine (n=51), the 2nd- rivaroxaban+ verapamil (n=30), the control group- rivaroxaban without CCBs (n=47). A trough steady-state plasma concentration (C min,ss) of rivaroxaban, prothrombin time (PT) in the blood plasma and the event of clinically relevant non-major (CRNM) bleeding were assessed for each patient. Results Patient in group 2 had higher C min,ss of rivaroxaban, PT and CRNM than subjects in the control group (Me 73.8 [50.6-108.8] ng/mL vs. 40.5 [25.6-74.3] ng/mL; Me 14.8 [13.4-17.3] s vs. 13.8 [12.6-14.4] s; 34% vs. 13%, respectively, p<0.05 for all). When compared, the PT and complication rate in group 1 with the control group C min,ss of rivaroxaban were practically the same (p>0.05 for all). Conclusions In patients≥80 years with NAF, the use of rivaroxaban in combination with verapamil may not be safe and can lead to CRNM bleeding.

Analysis of bioMARKer Distribution and Individual Reproducibility Under Rivaroxaban Treatment in Japanese Patients with Non-Valvular Atrial Fibrillation (R-MARK Study, CVI ARO2).

The "on-therapy range" of direct oral anticoagulants is the 90% interval of drug concentration. Previously, we reported the on-therapy range of rivaroxaban in a single-center cohort. The present study aimed to confirm the range and intraindividual reproducibility in a multicenter cohort.Eligible patients with non-valvular atrial fibrillation under rivaroxaban treatment for prevention of ischemic stroke were enrolled from nine institutes in Tokyo, Japan, between June 2016 and May 2017 (n = 324). The first and second (three months later) blood samples both taken within 1-5 hours after rivaroxaban intake were analyzed (n = 219). Plasma concentration of rivaroxaban (PC-Riv) and prothrombin time (PT) with five reagents were measured.The 90% interval of PC-Riv was 47.3-532.9 ng/mL. The 90% interval of PT measured with RecombiPlasTin 2G was 11.8-22.3 seconds, the widest range among the five reagents examined. PC-Riv reproducibility within a 90% interval was evaluated bidirectionally (first-to-second and second-to-first), and 92.4% of samples were reproducible. The change rate (CR) of PC-Riv between two samplings ranged widely, and high CR (≥54.3%, cutoff for predicting non-reproducibility) was predicted by concomitant drugs (non-dihydropyridine calcium antagonist and thiazide) and mitral regurgitation.We reported the on-therapy range of rivaroxaban in a multicenter cohort. This range was consistent with that of a single-center cohort and was highly reproducible within three months in daily clinical practice. However, caution is necessary regarding several factors that may affect the intraindividual variation of PC-Riv.

Transitioning hospitalized patients from rivaroxaban or apixaban to a continuous unfractionated heparin infusion: A retrospective review.

To determine a patient's clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin infusion. A retrospective chart review was conducted to investigate how unfractionated heparin infusions were managed at a tertiary care hospital in the setting of recent apixaban or rivaroxaban administration. Patients were separated into 2 cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. The primary composite outcome was total number of bleeding and thrombotic events; the secondary composite outcome was average incidence of heparin infusion holds and rate changes per patient. Data were collected from 76 patients (heparin anti-Xa = 69, aPTT = 7). Due to the limited number of patients within the aPTT cohort, this data was excluded from the analysis, and heparin anti-Xa descriptive statistics were reported without statistical comparisons. In the heparin anti-Xa group, a total of 10 bleeds and 1 thrombus were discovered. Additionally, the average number of infusion holds and rate changes was 0.841 and 2.65 times per patient, respectively, for those patients monitored via heparin anti-Xa assay. In the presence of a recently administered oral anti-Xa anticoagulant, more down-titrations occurred in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, and most up-titrations occurred after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy.

Effects of rivaroxaban and dabigatran on global hemostasis in patients with atrial fibrillation.

: The study was aimed to evaluate the effects of two standard doses of rivaroxaban and dabigatran on global hemostatic assays in patients with atrial fibrillation. The study included 52 patients treated with rivaroxaban (15/20 mg), 50 on dabigatran (110/150 mg) and 20 healthy individuals. Platelet-poor plasma was used for determination of three global hemostatic assays, namely endogenous thrombin potential (ETP), calibrated automated thrombogram (CAT) and overall hemostasis potential (OHP). Rivaroxaban and dabigatran reduced ETP (P < 0.01) although OHP (P < 0.05) was diminished only by dabigatran. Strong correlations were noticed between ETP parameters and the plasma concentrations of rivaroxaban (ETP, r = -0.51; c-max, r = -0.85; t-lag, r = 0.83; t-max, r = 0.66) as well as with plasma concentration of dabigatran (ETP, r = -0.75; c-max, r = -0.74; t-lag, r = 0.73; t-max, r = 0.52). Analysis of dabigatran concentrations under 50 ng/ml showed that ETP parameter has area under the concentration-time curve-receiver operating characteristic value of 0.879 (95% confidence interval 0.776-0.980). Dabigatran treatment paradoxically increased area under the concentration-time curve and peak values although rivaroxaban decreased peak values (P < 0.01). However, significant correlation between CAT parameters and plasma concentration of both direct oral anticoagulants was not observed. We confirmed that the CAT assay is inappropriate for estimation of dabigatran effects and is not fully sensitive as regards rivaroxaban. The ETP assay can potentially be the appropriate method for estimation of global hemostatic capacity as regards both direct oral anticoagulants. The role of OHP needs to be confirmed in additional studies. ETP parameter of chromogenic assay has promising potential in exclusion of high plasma concentrations of dabigatran.

Laboratory monitoring of rivaroxaban in Chinese patients with deep venous thrombosis: a preliminary study

BackgroundRivaroxaban, a novel oral anticoagulant drug, is widely used in clinical practice. There is no standardized laboratory monitoring for rivaroxaban, and its plasma concentration in Chinese patients with deep vein thrombosis is unclear. The rivaroxaban concentrations in human plasma and determine the steady-state concentration of rivaroxaban in patients with deep vein thrombosis are needed.MethodsAn ultra-high-performance liquid chromatography with mass spectrometric detection method was developed. Chromatographic separation was performed on a Waters BEH C18 column with isocratic elution using a mobile phase composed of acetonitrile and water. Quantitation of the analytes was performed using positive ionization mode and mass transitions of m/z 437.3 → m/z 145.0 and m/z 440.1 → m/z 145.0 for rivaroxaban and the internal standard, respectively. Blood samples were collected at 0 h and 2 h after patients took rivaroxaban for 7 days or more.ResultsThe method was validated over the concentration range of 0.5 ~ 400 ng•mL− 1 with a very low limit of quantification of 0.5 ng·mL− 1, and the intra- and inter-day precision (RSD%) were < 15%. The range of the steady state concentration in patients that took 15 mg rivaroxaban twice daily, 10 mg twice daily, 20 mg once daily, 15 mg once daily, and 10 mg once daily were 168.5 ~ 280.1 ng•mL− 1, 74.2 ~ 271.4 ng•mL− 1, 25.7 ~ 306.8 ng•mL− 1, 24.5 ~ 306.4 ng•mL− 1, and 15.4 ~ 229.2 ng•mL− 1, respectively.ConclusionsThe plasma rivaroxaban concentration in patients who took 10 mg rivaroxaban twice daily fluctuated less than that in patients who took 20 mg rivaroxaban once daily. The plasma concentration can be used for therapeutic drug monitoring for rivaroxaban.

Effects of direct oral anticoagulants on thromboelastographic parameters and fibrin clot properties in patients with venous thromboembolism.

Data concerning the impact of direct oral anticoagulants (DOACs) on the thromboelastography (TEG) indices in venousthromboembolism (VTE) patients are limited. The goal of this study was to compare the impact of DOACs on clot properties measured in whole blood using TEG kaolin test and in plasma obtained from real-life VTE patients. We assessed 53 patients, including 20 on rivaroxaban, 20 on apixaban, and 13 on dabigatran. Using the TEG® 5000, coagulation status was evaluated in whole blood samples, while plasma fibrin clot permeability (Ks) and its susceptibility to lysis (CLT) were assessed in citrated plasma. Plasma concentrations of rivaroxaban (99 [48 - 311] ng/ml) and apixaban (85 [40 - 105] ng/ml) were positively associated with Ks and inversely with CLT, while dabigatran concentrations (71 [39 - 98] ng/ml) correlated positively with Ks. Moreover, Ks was associated with clot formation times (R and K), time to maximum clot strength (TMA), coagulation index (CI) reflecting the overall coagulation status, and whole blood clot lysis time (TEG-CLT). Blood clot lysis index (CL30) was associated with plasma CLT in all patients on DOACs, while TMA correlated with CLT only in patients on apixaban. Higher DOAC concentrations were associated with longer retardation of whole blood clot formation and longer time needed to reach maximum level of its strength as well as with more permeable clots. We concluded that plasma fibrin clot properties correlate with corresponding TEG indices suggesting that TEG might be helpful in providing prognostic information about DOAC influence in VTE patients.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the prevention of venous thromboembolism

Anticoagulant plasma concentrations and patient characteristics might affect the benefit–risk balance of therapy. The study objective was to assess the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism (VTE) prophylaxis (VTE-P) after hip/knee replacement surgery. Post hoc exposure–response analyses were conducted using data from the phase 3 RECORD1–4 studies, in which 12,729 patients were randomized to rivaroxaban 10 mg once daily or enoxaparin for ≤ 39 days. Multivariate regression approaches were used to correlate model-predicted individual rivaroxaban exposures and patient characteristics with outcomes. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and by making use of the known correlation between rivaroxaban plasma concentration and dynamics of PT. No significant associations between rivaroxaban exposure and total VTE or major bleeding were identified. A significant association between exposure and a composite of major or non-major clinically relevant (NMCR) bleeding from day 4 after surgery was observed. The relationship was shallow, with an approximate predicted absolute increase in a composite of major or NMCR bleeding from 1.08 [95% confidence interval (CI) 0.76–1.54] to 2.18% (95% CI 1.51–3.17) at the 5th and 95th percentiles of trough plasma concentration, respectively. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit–risk could be identified within the investigated exposure range. Hence, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-P.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism

Anticoagulant plasma concentrations and patient characteristics might affect the benefit–risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN–DVT and EINSTEIN–PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure–response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure–efficacy relationships were shallow. Exposure–safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit–risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation

Rivaroxaban exposure and patient characteristics may affect the rivaroxaban benefit–risk balance. This study aimed to quantify associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation (NVAF), using data from the phase 3 ROCKET AF trial (NCT00403767). In ROCKET AF, 14,264 patients with NVAF were randomized to rivaroxaban (20 mg once daily [OD], or 15 mg OD if creatinine clearance was 30–49 mL/min) or dose-adjusted warfarin (median follow-up: 707 days); rivaroxaban plasma concentration was measured in a subset of 161 patients. In this post hoc exposure–response analysis, a multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event efficacy and safety outcomes in 7061 and 7111 patients, respectively. There was no significant association between model-predicted rivaroxaban trough plasma concentration (Ctrough) and efficacy outcomes. Creatinine clearance and history of stroke were significantly associated with efficacy outcomes. Ctrough was significantly associated with the composite of major or non-major clinically relevant (NMCR) bleeding (hazard ratio [95th percentile vs. median]: 1.26 [95% confidence interval 1.13–1.40]) but not with major bleeding alone. The exposure–response relationship for major or NMCR bleeding was shallow with no clear threshold for an acceleration in risk. History of gastrointestinal bleeding had a greater influence on safety outcomes than Ctrough. These results support fixed rivaroxaban 15 mg and 20 mg OD dosages in NVAF. Therapeutic drug monitoring is unlikely to offer clinical benefits in this indication beyond evaluation of patient characteristics.

Study on the evaluation of Rivaroxaban′s blood concentration by anti-FX activity assay

Objective The anti-FⅩa assay can be used to monitor the blood concentration of Rivaroxaban. The aim is to evaluate the critical value and diagnostic performance of this test on bleeding risk assessment. Methods From September 2017 to June 2019, 368 patients were enrolled for retrospective cohort study, including 201 males and 167 females, aged (62.8±15.7) years old. They were divided into groups by age:≤60 years old group 105 cases,61-70 years old group 135 cases,≥71 years old group 128 cases. Anti-FⅩa was detected on ACL TOP 700 coagulation analyzer using chromogenic substrate method to quantitatively determine the plasma concentration of rivaroxaban. Anti-FⅩa data were expressed as M (P25-P75);Kruskal-Wallis H test was used for comparison among groups; Mann-Whitney U test was for data comparison between two groups; positive rate comparison was performed by χ2 test; the diagnostic performance of anti-FⅩa to assess bleeding risk was evaluated by ROC curve;Kaplan-Meier curve was used for the survival analysis;the risk ratio (HR) was obtained by Cox proportional hazard regression model. Results Both the peak and trough plasma concentrations were higher in patients aged 61-70 years old than ≤60 years old (U values were 5 618 and 5 725,respectively, P values were 0.006 and 0.011, respectively); higher in patients ≥71 years old than 61-70 years old (U values were 6 438 and 6 317, respectively, P values were 0.05).Both peak and trough blood concentrations were higher in patients with bleeding than without bleeding(U values were 1 429 and 2 185, respectively, P<0.001 and 0.001, respectively).ROC showed that the cut-off values of peak blood concentration in evaluation of the overall and the ≥61 year-old population′s bleeding risk were 200.8 ng/ml and 209.9 ng/ml,respectively, corresponding respectively with the sensitivity of 90.9% and 95.0%; the trough cut-off values were 35.1 ng/ml and 39.1 ng/ml, respectively, corresponding respectively with the sensitivity of 72.7% and 70.0%. However, all the above cut-off values gave a low diagnostic specificity. Survival analysis showed with 35.1 ng/ml as the trough cut-off value, the cumulative risk of bleeding significantly increased in patients above the cut-off value (Log-rank χ2=4.513,P=0.034). The Cox proportional regression model demonstrated that the hazard ratios for peak and trough blood concentration predictions of bleeding risk were 1.023 (95%CI: 0.834-1.256) and 0.948 (95%CI: 0.773-1.164). respectively. Conclusions Both the peak and trough values of blood concentration in bleeding patients are higher than non-bleeding patients. The peak blood concentration is highly sensitive to the risk of bleeding, and the elevated trough blood concentration levels indicate that the probability of bleeding risk increases in the short term. However, the specificity of both peak and trough values is relatively low in bleeding risk assessment. When used alone, the prediction of bleeding events does not have direct guiding significance. Dynamic monitoring and joint evaluation are recommended. Key words: Factor Ⅹa; Rivaroxaban; Plasma concentration; Blood coagulation tests; Hemorrhage; Forecasting

Can an anti-Xa assay for unfractionated heparin be used to assess the presence of rivaroxaban in critical situations?

ObjectiveAlthough rivaroxaban has recently become widely used for thrombosis treatment, it is difficult for clinicians to make clinical decisions in critical situations, such as emergent surgery or interventions, because a specific anti-Xa assay is not available in many laboratories. This study assessed the relationships between rivaroxaban-specific anti-factor Xa activity (AXA) and unfractionated heparin (UFH)-specific AXA and determined the cutoff level for UFH-specific AXA in critical situations for patients undergoing rivaroxaban therapy. MethodsThirty-eight blood samples were collected from patients with cancer-associated thrombosis receiving rivaroxaban therapy. All samples were assessed using both rivaroxaban-specific and UFH-specific anti-Xa assays. Routine coagulation studies, including prothrombin time (PT) and activated partial thromboplastin time, were also conducted on the samples. ResultsA positive dose-dependent correlation between rivaroxaban-specific and UFH-specific AXA was evident (R = 0.97; P < .0001). Rivaroxaban-specific AXA was also positively correlated with PT (R = 0.95; P < .0001) but only weakly with activated partial thromboplastin time (R = 0.67; P < .0001). Patients with plasma rivaroxaban concentrations <100 ng/mL were found to have UFH-specific AXA <1.41 IU/mL and PT <17.3 seconds, with sensitivities of 100% and 93.3% and specificities of 87.0% and 95.7%, respectively. ConclusionsOur study demonstrates that UFH-calibrated AXA correlates strongly with plasma rivaroxaban concentration. This assay appears to be sensitive to the presence of rivaroxaban, which may be advantageous in the setting of assessing drug levels for critical events. These findings suggest that if a rivaroxaban-specific anti-Xa assay is unavailable, the chromogenic anti-Xa assay for UFH may be useful to assess the anticoagulant effects of rivaroxaban.

Using the PCI-IS Method to Simultaneously Estimate Blood Volume and Quantify Nonvitamin K Antagonist Oral Anticoagulant Concentrations in Dried Blood Spots.

Nonvitamin K antagonist oral anticoagulants (NOACs) have emerged as the preferred choice for the treatment of atrial fibrillation (AF). The establishment of a therapeutic range to minimize bleeding and thrombosis is important for personalized treatment of NOACs. The importance of dried blood spots (DBSs) has increased in medical care. An efficient and effective DBS analytical method could facilitate the concentration management of NOACs. The postcolumn infused internal standard (PCI-IS) method was applied to estimate spot volume and quantify dabigatran, rivaroxaban, and apixaban concentrations on DBS cards. The extraction solvent contented 0.1% formic acid and 70% ACN with a successive extraction procedure. Paired DBS and plasma samples from patients undergoing NOAC therapy (n = 269) were used to calculate conversion factors. [13C6]-Rivaroxaban was selected as the PCI-IS. The quantification accuracy for the three NOACs was within 88.9-104.3%. The RSDs of the repeatability and intermediate precision were below 10%. The obtained conversion factors of DBS to plasma concentrations of dabigatran, apixaban, and rivaroxaban were 1.81, 1.59, and 1.31, respectively. Bland-Altman analysis showed that the % differences between predicted and measured plasma concentrations were within a bias of ±20%. The result showed that PCI-IS was an accurate and efficient LC-MS/MS method to simultaneously estimate blood volume and NOAC concentrations on DBS cards. The stability results revealed that the DBS sampling strategy could improve compound stability. The developed method offers a new strategy for the therapeutic drug monitoring of NOACs and may improve the safe use of these drugs.

Standard coagulation assays alone are not sufficient to exclude surgically relevant rivaroxaban plasma concentrations

BackgroundWhile mainly larger hospitals have introduced routine anti-Xa assays for rivaroxaban (RXA), these are not readily available to smaller hospitals often relying on routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT).The aim of our study was to investigate the effect of RXA plasma concentration on the standard coagulation tests PT (Quick test and INR) and aPTT in a large group of real-life patients. We further assessed whether normal results of these standard coagulation assays are sufficient to exclude surgically relevant RXA plasma concentration, defined as > 50 mcg/l.MethodsThis retrospective study included all patients between 2012 and 2016 where anti-Xa (calibrated for RXA), PT (Quick test and INR), and/or aPTT were determined from the same sample. PT is expressed as Quick value (% of normal plasma pool). In total, 1027 measurements in 622 patients were eligible for analysis: 752 measurements of 505 patients for Quick/INR and 594 measurements of 417 patients for aPTT.ResultsA moderate correlation of PT/Quick (Pearson's correlation coefficient − 0.59; p < 0.001), INR (Pearson's correlation coefficient 0.5; p < 0.001), and aPTT (Pearson's correlation coefficient 0.53; p < 0.001) with RXA plasma concentration was observed. However, in 50% of all samples with a normal PT/Quick, in 25% of all samples with a normal INR and in 80% of all samples with a normal aPTT residual RXA plasma concentration was surgically relevant.ConclusionAlthough a moderate correlation of RXA plasma concentration with PT/Quick, INR, and aPTT was observed, standard coagulation assays are not sufficient to exclude surgically relevant RXA plasma concentrations.

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

BackgroundRivaroxaban 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. MethodsSixty 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. ResultsThrombin 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. ConclusionsThis 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.

Enhancing the Quality of Rivaroxaban Exposure Estimates Using Prothrombin Time in the Absence of Pharmacokinetic Sampling.

Prothrombin time (PT) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic (PK) data to provide individual exposure measures for input into rivaroxaban exposure–response analyses, the aim of the present study was to investigate the use of PT‐adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT‐adjustment approaches were established using time‐matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT‐adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate‐only exposure estimates.

The rivaroxaban-adjusted normalized ratio: use of the prothrombin time to monitor the therapeutic effect of rivaroxaban

ABSTRACTBackground: The prothrombin time may be used to monitor the plasma concentration of rivaroxaban. However, there is variability in the responsiveness of rivaroxaban to different thromboplastins. We aimed to develop a rivaroxaban-monitoring method using the prothrombin time to reduce the differences in the sensitivity among reagents.Methods: Rivaroxaban-spiked pooled normal plasma at a 0–1000 ng/ml concentration was used to generate a rivaroxaban-adjusted sensitivity index (SI) values, and was tested with three thromboplastins. The warfarin-adjusted international sensitivity index (ISI-warfarin), rivaroxaban-adjusted sensitivity index (SI-rivaroxaban), international normalized ratio (INR) calculated with ISI-warfarin, normalized ratio (NR) calculated with SI-rivaroxaban, and their coefficient of variances (CVs) were compared. The NR-rivaroxaban value was compared with the results of an anti-Xa assay.Results: The ISI-warfarin and SI-rivaroxaban using different thromboplastins were 1.02 and 1.88, respectively, with Thromborel S, 0.90 and 1.00 using Recombiplastin 2G, and 1.30 and 1.15 using Neoplastin CI-plus. Between-thromboplastin variability expressed as CV were 6.3%–25.1% when expressed as INR-warfarin and 1.7%–4.7% when expressed as NR-rivaroxaban. CVs for the NR-rivaroxaban with another laboratory were significantly lower than those for INR-warfarin. Anti-Xa assay v NR-rivaroxaban correlation coefficients were 0.97–0.99.Conclusion: Using a rivaroxaban-specific NR effectively minimises inter-thromboplastin variability. By utilizing a NR-rivaroxaban, standardized prothrombin time results could be rapidly obtained, especially useful in standardizing the therapeutic effect of rivaroxaban.

Intra- and inter- individual rivaroxaban concentrations and potential bleeding risk in patients with atrial fibrillation.

Routine laboratory monitoring of rivaroxaban and dose adjustment relating to exposure is currently not recommended. However, in certain clinical situations, assessment of rivaroxaban levels is desirable. To examine inter- and intra-subject plasma rivaroxaban variability in patients with atrial fibrillation (AF) and to correlate these results to clinical outcomes. We included 60 patients with AF treated with rivaroxaban: half on 20mg daily (R20) and half on 15mg daily (R15). Three trough and peak blood samples were collected with an interval of 6-8weeks apart. Plasma rivaroxaban concentration was measured directly by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and indirectly by anti-Xa for rivaroxaban, prothrombin time (PT), and activated partial thromboplastin time (APTT). Patients on R15 were older (76 ± 6 vs 71 ± 6years), had lower creatinine clearance (60 ± 26 vs 99 ± 32mL/min), higher CHADS2 (2.5 ± 1.2 vs 1.8 ± 1.3), all p < 0.01, but had similar rivaroxaban concentrations in trough samples to patients on R20. There was no significant intra-individual variability for trough or peak rivaroxaban concentration assessed by LC-MS/MS, anti-Xa, or PT. Trough rivaroxaban levels determined by LC-MS/MS (48 ± 30 vs 34 ± 26, p = 0.02) and anti-Xa, but not with PT and APTT, were higher in patients with bleeding than in patients without it. There is a pronounced inter-, but not intra-individual variability in the rivaroxaban trough levels in patients with AF. Assessment of trough rivaroxaban concentration with LC-MS/MS or anti-Xa, but not with APTT or PT, may help to identify patients at increased risk of bleeding.