Pharmacokinetic evaluation of rivaroxaban for the treatment of acute coronary syndromes

Gopalakrishnan, Lakshmi; Kumar, Varun; Kohli, Payal; Singh, Priyamvada; Rastogi, Ujjwal; Gibson, C. Michael

doi:10.1517/17425255.2012.688026

Cited by 4 publications

(12 citation statements)

References 58 publications

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“…Furthermore, Mueck et al reported that the PT correlated almost linearly with rivaroxaban concentrations below 500 ng/ml 37 . In addition, a linear intercept model with a declining exponent and correlation of PT with the logarithm of the rivaroxaban plasma concentration was reported previously 27,30,38 …”

Section: Discussionmentioning

confidence: 83%

Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients

Esmaeili

Rezaee

Esfahani

et al. 2022

Clinical Pharmacy Therapeu

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What is Known and Objective Although predictable pharmacokinetic and pharmacodynamic of rivaroxaban allow fixed dosing regimens without routine coagulation monitoring, there is still the necessity to monitor and predict the effects of rivaroxaban in specific conditions and different populations. The current study was designed and conducted to analyze the rivaroxaban population pharmacokinetics in Iranian patients and establish a pharmacokinetic/pharmacodynamic model to predict the relationship between rivaroxaban concentration and its anticoagulant activity. Methods A sequential nonlinear mixed effect pharmacokinetic/pharmacodynamic modeling method was used to establish the relation between rivaroxaban concentration and anti‐factor Xa activity, prothrombin time, and activated partial thromboplastin time (aPTT) as pharmacodynamic biomarkers in a population of sixty‐nine Iranian patients under treatment with oral rivaroxaban. Rivaroxaban plasma concentration was quantified by a validated high‐performance liquid chromatography‐tandem mass spectrometry. Results and Discussion The typical population values (inter‐individual variability%) of the oral volume of distribution and clearance for a one‐compartment model were 61.2 L (21%) and 3.68 L·h−1 (61%), respectively. Creatinine clearance and Child‐Turcotte‐Pugh score were found to affect the clearance. A direct link linear structural model best fitted the data for both prothrombin time and aPTT. The baseline estimates of aPTT and prothrombin time in the population were 35.0 (15%) and 12.6 (2%) seconds, respectively. The slope of the relationship between apTT, prothrombin time, and rivaroxaban concentration was 0.033 (28%) and 0.018 (54%) s·ml·ng−1, respectively. The selected model for anti‐factor Xa activity consisted of a direct link inhibitory Emax model with Hill coefficient. The maximum level of inhibition (Emax) was 4 IU·ml−1. The concentration of rivaroxaban producing 50% of the maximum inhibitory effect (EC50) was 180 (24%) ng·ml−1, and Hill coefficient (γ) was 1.44 (108%). No covariates showed a statistically significant effect on PT and activated partial thromboplastin time prolonging properties and anti‐factor Xa activity. What is New and Conclusion Our results confirmed that pharmacokinetic/pharmacodynamic models similar to those of the other studies describe the relationship between the rivaroxaban concentration and its anticoagulant effect in Iranian patients. However, considerable differences were observed in the parameters of the pharmacodynamics–pharmacokinetic models with the results of other reports that can explain the unpredictable effects of rivaroxaban in some patients.

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Section: Discussionmentioning

confidence: 83%

Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients

Esmaeili

Rezaee

Esfahani

et al. 2022

Clinical Pharmacy Therapeu

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“…It has dose-proportional pharmacokinetics with an oral bioavailability of approximately 80% [37]. The half-life is 5-13 h (5-9 h in the young and 11-13 h in the elderly) and the time to peak concentration in plasma is 2-4 h, which correlates well with the time for maximum inhibition of factor Xa [38]. The inhibition of factor Xa persists for up to 24 h after administration of a dose of rivaroxaban.…”

Section: Oral Factor Xa Inhibitors In Acsmentioning

confidence: 99%

“…a creatine clearance of <15 ml/min), and the dose needs to be adjusted in patients with advanced renal insufficiency (i.e. a creatine clearance of 15-29 ml/min) [38,40]. …”

Section: Oral Factor Xa Inhibitors In Acsmentioning

confidence: 99%

Role of Oral Factor Xa Inhibitors after Acute Coronary Syndrome

et al. 2014

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Despite an early invasive strategy and the use of dual antiplatelet therapy, patients with acute coronary syndrome (ACS) continue to be at substantial risk for recurrent ischemic events. It is believed that this risk is, at least in part, due to an intrinsic coagulation pathway that remains activated for a prolonged period after ACS. Earlier studies using warfarin showed a reduction in ischemic events, but the overall benefits were offset by increased bleeding complications. Recently, there has been increased interest in the potential role of new oral anticoagulants, some of which target factor Xa, after ACS. Factor Xa is important for the coagulation pathway and also plays a role in cellular proliferation and inflammation. It may thus be an attractive target for therapeutic intervention in ACS. Recently, various oral factor Xa inhibitors have been studied as potential treatment options for ACS. This review will focus on currently available data to evaluate the possible role of factor Xa inhibitors in the management of patients with ACS.

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“…drug-drug interactions, metabolism, naringenin, pharmacokinetic, rivaroxaban F I G U R E 1 Chemical structures of rivaroxaban, rivaroxaban metabolite M2, M1, naringenin, and diazepam inducers or inhibitors of CYP3A4, 12,23,24 the purpose of the current study is to evaluate whether some drug-drug interactions are existed between naringenin and rivaroxaban in rats both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that naringenin can influence the pharmacokinetics and metabolism of other drugs when co‐administrated with those drugs metabolized by CYP3A4 (such as tofacitinib, ibrutinib, and felodipine) 20–22 . Considering that rivaroxaban can be influenced by inducers or inhibitors of CYP3A4, 12,23,24 the purpose of the current study is to evaluate whether some drug–drug interactions are existed between naringenin and rivaroxaban in rats both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Naringenin has an inhibitory effect on rivaroxaban in rats both in vitro and in vivo

Shi

Zhao

Chen

et al. 2021

Pharmacology Res & Perspec

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Food–drug interactions are reported to have some impacts on the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of naringenin, one natural product in many fruits, on the pharmacokinetics of rivaroxaban, drug–drug interactions (DDIs) between naringenin and rivaroxaban in vitro were investigated in Sprague–Dawley (SD) rat liver microsomes. For the DDIs in vivo, 12 male SD rats were randomly divided into the experimental group and the control group with six rats in each group. Rats in the experimental group were pre‐treated with naringenin (10 mg/kg/day) for 2 weeks before the administration of rivaroxaban (10 mg/kg) by oral gavage, while the rats in the control group were given rivaroxaban (10 mg/kg) only once. The plasma concentration of rivaroxaban in rats was then measured by UPLC‐MS/MS. In vitro data indicated that naringenin could decrease the metabolic clearance rate of rivaroxaban with the IC 50 value of 38.89 μM, and exhibited a mixed inhibition to rivaroxaban (Ki =54.91 μM, aKi =73.33 μM, a = 0.74). In vivo data in rats revealed that as compared with that of the control group, the AUC (0– t ) value of rats in the experimental group was increased from 2406.28 ± 519.69 μg/h/L to 4005.04 ± 1172.76 μg/h/L, the C max value was increased from 310.23 ± 85.76 μg/L to 508.71 ± 152.48 μg/L, and the V z / F and CL z / F were decreased from 23.03 ± 4.81 L/kg to 16.2 ± 8.42 L/kg, 4.26 ± 0.91 L/h/kg to 2.57 ± 0.73 L/h/kg, respectively. These data indicated that naringenin had an inhibitory effect on the pharmacokinetics of rivaroxaban in rats, suggesting that the DDIs between naringenin and rivaroxaban might occur when they were co‐administered in the clinic.

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Pharmacokinetic evaluation of rivaroxaban for the treatment of acute coronary syndromes

Cited by 4 publications

References 58 publications

Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients

Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients

Role of Oral Factor Xa Inhibitors after Acute Coronary Syndrome

Naringenin has an inhibitory effect on rivaroxaban in rats both in vitro and in vivo

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