Perpetrator effects of ciclosporin (P‐glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers

Brings, Antonia; Lehmann, Marie‐Louise; Foerster, Kathrin I.; Burhenne, Jürgen; Weiß, Johanna; Haefeli, Walter E.; Czock, David

doi:10.1111/bcp.13934

Cited by 28 publications

(23 citation statements)

References 36 publications

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“…6 Area under the concentration–time curve ratios (AUCR) and maximum (peak) concentration ratios ( C max R) of rivaroxaban with and without concomitantly taken drugs. Results of drug–drug interaction trials that have been conducted and published up to January 2020 are depicted [ 62 , 63 , 69 , 74 , 81 – 83 , 98 , 104 , 118 – 122 ]. A ratio equals 1 if the co-administered drug statistically insignificantly influenced direct oral anticoagulant (DOAC) pharmacokinetics.…”

Section: Basics Of Doac Pharmacokineticsmentioning

confidence: 99%

Drug–Drug Interactions with Direct Oral Anticoagulants

et al. 2020

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A large body of evidence suggests that not only direct anticoagulant effects but also major bleeding events and stroke prevention depend on plasma concentrations of direct oral anticoagulants (DOACs). Concomitant drugs that cause drug-drug interactions (DDIs) alter DOAC exposure by increasing or decreasing DOAC bioavailability and/or clearance; hence, they might affect the efficacy and safety of DOAC therapy. Patients with renal impairment already receive smaller DOAC maintenance doses because avoidance of elevated DOAC exposure might prevent serious bleeding events. For other causes of increased exposure such as DDIs, management is often less well-defined. Considering that DOAC patients are often older and have multiple co-morbidities, polypharmacy is highly prevalent. However, the effect of multiple drugs on DOAC exposure, and especially the impact of DDIs when concurring with drug-disease interactions as observed in renal impairment, has not been thoroughly elucidated. In order to provide effective and safe anticoagulation with DOACs, understanding the mechanisms and magnitude of DDIs appears relevant. Instead of avoiding drug combinations with DOACs, more DDI trials should be conducted and new strategies such as dose adjustments based on therapeutic drug monitoring should be investigated. However, dose adjustments based on concentration measurements cannot currently be recommended because evidence-based data are missing.

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Section: Basics Of Doac Pharmacokineticsmentioning

confidence: 99%

Drug–Drug Interactions with Direct Oral Anticoagulants

et al. 2020

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“…Thus, patients treated with single modulators of multiple elimination pathways or multiple modulators of single-elimination pathways (CYP3A, P-gp) need extra care, both in daily practice and also in drug labels. 4 After an oral dose of 10 mg rivaroxaban, the metabolite profile in human plasma showed unchanged rivaroxaban concentration. Neither major nor active circulating metabolites were present in the main compound.…”

mentioning

confidence: 99%

“…The addition of fluconazole increased the average exposure of rivaroxaban further. Thus, patients treated with single modulators of multiple elimination pathways or multiple modulators of single‐elimination pathways (CYP3A, P‐gp) need extra care, both in daily practice and also in drug labels …”

mentioning

confidence: 99%

Bioequivalence Study of 2 Formulations of Rivaroxaban, a Narrow‐Therapeutic‐Index Drug, in Healthy Chinese Subjects Under Fasting and Fed Conditions

Ding

Wang

Xie

et al. 2019

Clinical Pharm in Drug Dev

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This study aimed to evaluate the bioequivalence (BE) of 2 formulations of the 10‐mg rivaroxaban tablet. The study was a randomized, open‐label, 4‐period, crossover study that included 28 healthy subjects in fasting or fed conditions. The pharmacokinetic parameters were determined based on the concentrations of rivaroxaban using high‐performance liquid chromatography with a tandem mass spectrometer detector. In each of the 4 study periods with fasting or fed conditions, a single dose of test or reference product was administered. Rivaroxaban concentrations in plasma were determined using a validated liquid chromatography with a tandem mass spectrometer detector method. The pharmacokinetic parameters assessed were the area under the plasma concentration‐time curve (AUC0‐t, AUC0‐∞), the peak plasma concentration of the drug (Cmax), time to achieve Cmax, elimination half‐life, within‐subject variability of test drug, and within‐subject variability of reference drug. The geometric mean ratio (90%CI) of the test drug/reference drug for rivaroxaban was 90.38% to 103.60% for AUC0‐t in fasting conditions and 90.13% to 100.42% in fed conditions. The AUC0‐∞s were 89.94% to 102.50% and 90.14% to 100.45% under fasting and fed conditions, respectively. The Cmax values were 90.58% to 105.01% and 96.36% to 108.07% in these 2 conditions, respectively. All 90%CIs for test drug/reference drug geometric mean ratio were ≤2.5. The 90%CIs for test/reference AUC ratio and Cmax ratio were within the acceptable range for BE. There were no adverse events encountered during this BE study. The study's results indicated that the 2 formulations of the rivaroxaban tablet were bioequivalent.

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“…The study of effect of a potent P-gp inhibitor cyclosporin and its combination with a moderate CYP3A inhibitor fluconazole on pharmacokinetics of rivaroxaban and CYP3A activity (compared with baseline) showed that cyclosporine increased average exposure of rivaroxaban by 47%, maximum concentration of CYP3A4 and decreased by 34%, and cyclosporine in combination with fluconazole increased the average exposure of rivaroxaban by 86% and maximum concentration by 115%. This effect was significantly stronger than that observed in control group that received rivaroxaban with fluconazole alone [57].…”

Section: Rivaroxabanmentioning

confidence: 61%

Pharmacogenetics of Direct Oral Anticoagulants

Shnayder¹,

Петрова²,

Bochanova³

et al. 2021

Pharmacogenetics

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For more than 50 years, oral vitamin K antagonists were the choice of anticoagulant for the long-term treatment and prevention of arterial and venous thromboembolic events. In recent years, four direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban have been compared with warfarin for thromboembolism prevention. These anticoagulants directly inhibit specific proteins within the coagulation cascade; in contrast, oral vitamin K antagonists inhibit the synthesis of vitamin K-dependent clotting factors. Dabigatran, a direct thrombin inhibitor, and rivaroxaban, apixaban and edoxaban, the factor Xa inhibitors, produce a more predictable, less labile anticoagulant effect. DOACs do not have limitations inherent vitamin K antagonists. DOACs have a predictable pharmacokinetic profile and are free of advers drugs reactions inherent in vitamin K antagonists. However, it is necessary to take into account the pharmacogenetic characteristics of the individual that can affect effectiveness and safety of use of DOACs. The results carried out to the present fundamental and clinical studies of DOACs studies demonstrate an undeniable the influence of genome changes on the pharmacokinetics and pharmacodynamics of DOACs. However, the studies need to be continued. There is a need to plan and conduct larger studies in various ethnic groups with the inclusion of sufficient associative genetic studies of the number of patients in each of the documented groups treatments with well-defined phenotypes.

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Perpetrator effects of ciclosporin (P‐glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers

Cited by 28 publications

References 36 publications

Drug–Drug Interactions with Direct Oral Anticoagulants

Drug–Drug Interactions with Direct Oral Anticoagulants

Bioequivalence Study of 2 Formulations of Rivaroxaban, a Narrow‐Therapeutic‐Index Drug, in Healthy Chinese Subjects Under Fasting and Fed Conditions

Pharmacogenetics of Direct Oral Anticoagulants

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