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

Sychev, D. A.; Мирзаев, К. Б.; Chernyaeva, M. S.; Kulikova, Maria; Бочков, П. О.; Шевченко, Р. В.; Gorbatenkova, Svetlana; Головина, О. В.; Остроумова, О Д; Bahteeva, Damirya; Rytkin, Eric

doi:10.1515/dmdi-2020-0127

Cited by 6 publications

(3 citation statements)

References 32 publications

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“…In this study, we chose eleven commonly prescribed cardiovascular drugs for our first stage of DDI evaluation: verapamil, diltiazem, nifedipine, amlodipine, amiodarone, quinidine, propafenone, irbesartan, valsartan, benazepril and captopril (as a control drug not metabolized by liver enzymes). Unexpectedly, the preliminary in vitro evaluation results showed that amlodipine and nifedipine exhibited the highest inhibitory effect (with more than 5-fold) on vonoprazan, while other CYP3A4 inhibitors, verapamil, diltiazem and amiodarone only exhibited slightly increased inhibition effects, although they were reported to have the same ( Zhou, 2008 ) or even stronger ( Sychev et al, 2020 ) inhibition on CYP3A4 than that of amlodipine or nifedipine. Next, we evaluated the IC 50 values of amlodipine and nifedipine that reconfirmed their inhibition effects on vonoprazan in both RLMs and HLMs, showing a stronger inhibition in HLMs.…”

Section: Discussionmentioning

confidence: 97%

Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

Shi¹,

Dai²,

Cai³

et al. 2022

Front. Pharmacol.

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As a novel acid-suppressing drug, vonoprazan shows the potential to replace traditional proton-pump inhibitors. With its widespread use, some adverse effects that require further study have emerged due to drug–drug interactions. Our study is the first experiment that evaluated the drug–drug interactions of eleven common cardiovascular drugs that inhibit vonoprazan metabolism in vitro and in vivo. Rat liver microsome incubation and molecular simulation docking were applied to explore the inhibition mechanism. Amlodipine and nifedipine showed inhibitory effects on vonoprazan metabolism in both rat and human liver microsomes in the first evaluation part in vitro. The inhibition mechanism analysis results demonstrated that amlodipine and nifedipine might inhibit the metabolism of vonoprazan by a mixed type of competitive and non-competitive inhibition. However, the pharmacokinetic data of the vonoprazan prototype revealed that amlodipine affected vonoprazan in vivo while nifedipine did not. Thus, more attention should be paid when amlodipine is prescribed with vonoprazan. Furthermore, the changes in its carboxylic acid metabolites MI hinted at a complex situation. Molecular simulation suggested the CYP2B6 enzyme may contribute more to this than CYP3A4, and further inhibitory experiments preliminarily verified this speculation. In conclusion, the use of vonoprazan with cardiovascular drugs, especially amlodipine, should receive particular attention in clinical prescriptions.

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Section: Discussionmentioning

confidence: 97%

Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

Shi¹,

Dai²,

Cai³

et al. 2022

Front. Pharmacol.

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“…The risk of bleeding was evidenced shortly after DDIs exposure and logically increased over time. Some factors such advanced age, renal failure, or severe inflammatory syndrome can significantly modulate the magnitude of pharmacokinetic DDIs [63][64][65]. Furthermore, unexpected DDIs could occur.…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

Incidence, risk factors, and management of bleeding in patients receiving anticoagulants for the treatment of cancer-associated thrombosis

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Espósito

et al. 2021

Support Care Cancer

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Updated clinical practice guidelines recommend the long-term use of low-molecular-weight heparins or direct oral anticoagulants as the preferred option for the treatment of cancer-associated thrombosis (CAT), using a personalized approach matching the right drug to the right patient. In most cases, the benefit of anticoagulant therapy outweighs the risk. However, the long-term use of anticoagulants is associated with a non-negligible risk of bleeding, which constitutes a rare but serious adverse effect. Bleeding complications have been reported to be overall 2 to 3 times more frequent in cancer patients with CAT receiving anticoagulation than in non-cancer patients, with a reported incidence of major bleeding ranging from 2.4 to 16.0% in randomized controlled trials (RCT). In the absence of validated risk assessment model to predict the risk of bleeding in these patients, a careful evaluation of each individual profile, with adequate selection of the most appropriate anticoagulant for each individual patient, is warranted for overcoming management challenges, taking in account the numerous factors which may potentiate the overall bleeding risk in these complex patients, such as advanced or metastatic disease, older age, anemia, thrombocytopenia, renal impairment, liver dysfunction, and concomitant anticancer therapies. The purpose of this review is to call for awareness on bleeding complications as a major safety issue of CAT treatment and to summarize data from recent RCT and real-world studies on the incidence and risk factors for bleeding in this unique and challenging population to further help clinicians in decision-making. KeywordsCancer-associated thrombosis • Anticoagulants • Direct oral anticoagulants • Low-molecular-weight heparin • Bleeding * Nicolas Janus

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“…In the study on the effect of single nucleotide polymorphism of ABCB1 gene on in-vitro pharmacokinetics of rivaroxaban, it was shown that 3435C>T polymorphism of ABCB1 gene had no significant effect on intracellular accumulation of rivaroxaban compared to normal genotype [21]. In another study by Sychev et al [22] devoted to the assessment of the risk of interdrug interaction between rivaroxaban and slow calcium channel blockers in patients with nonvalvular atrial fibrillation over 80 years old, the data were obtained that in the group of patients taking rivaroxaban together with CYP3A4 and glycoprotein P inhibitor verapamil, prothrombin time, residual equilibrium concentration and the incidence of clinically significant minor bleeding were significantly higher compared with the group of patients taking rivaroxaban with amlodipine and the control group taking rivaroxaban alone [22].…”

Section: Introductionmentioning

confidence: 99%

Influence of ABCB1, CYP3A5 and CYP3A4 gene polymorphisms on prothrombin time and the residual equilibrium concentration of rivaroxaban in patients with non-valvular atrial fibrillation in real clinical practice

Сычев

Соколов

Reshetko

et al. 2022

Pharmacogenetics and Genomics

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Objective The study of ABCB1 and CYP3A4/3A5 gene polymorphism genes is promising in terms of their influence on prothrombin time variability, the residual equilibrium concentration of direct oral anticoagulants (DOACs) in patients with atrial fibrillation and the development of new personalized approaches to anticoagulation therapy in these patients. The aim of the study is to evaluate the effect of ABCB1 (rs1045642) C>T; ABCB1 (rs4148738) C>T and CYP3A5 (rs776746) A>G, CYP3A4*22(rs35599367) C>T gene polymorphisms on prothrombin time level and residual equilibrium concentration of rivaroxaban in patients with atrial fibrillation. Methods In total 86 patients (42 men and 44 female), aged 67.24 ± 1.01 years with atrial fibrillation were enrolled in the study. HPLC mass spectrometry analysis was used to determine rivaroxaban residual equilibrium concentration. Prothrombin time data were obtained from patient records. Results The residual equilibrium concentration of rivaroxaban in patients with ABCB1 rs4148738 CT genotype is significantly higher than in patients with ABCB1 rs4148738 CC (P = 0.039). The analysis of the combination of genotypes did not find a statistically significant role of combinations of alleles of several polymorphic markers in increasing the risk of hemorrhagic complications when taking rivaroxaban. Conclusion Patients with ABCB1 rs4148738 CT genotype have a statistically significantly higher residual equilibrium concentration of rivaroxaban in blood than patients with ABCB1 rs4148738 CC genotype, which should be considered when assessing the risk of hemorrhagic complications and risk of drug–drug interactions. Further studies of the effect of rivaroxaban pharmacogenetics on the safety profile and efficacy of therapy are needed.

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

Cited by 6 publications

References 32 publications

Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

Evaluation of commonly used cardiovascular drugs in inhibiting vonoprazan metabolism in vitro and in vivo

Incidence, risk factors, and management of bleeding in patients receiving anticoagulants for the treatment of cancer-associated thrombosis

Influence of ABCB1, CYP3A5 and CYP3A4 gene polymorphisms on prothrombin time and the residual equilibrium concentration of rivaroxaban in patients with non-valvular atrial fibrillation in real clinical practice

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