Monitoring of anti-Xa activity and factors related to bleeding events: A study in Japanese patients with nonvalvular atrial fibrillation receiving rivaroxaban

Sakaguchi, Teruhiro; Osanai, Hiroyuki; Murase, Yosuke; Ishii, Hideki; Nakashima, Yasuhiro; Asano, Hiroshi; Suzuki, Susumu; Takefuji, Mikito; Inden, Yasuya; Sakai, Kazuyoshi; Murohara, Toyoaki; Ajioka, Masayoshi

doi:10.1016/j.jjcc.2016.11.013

Cited by 41 publications

(40 citation statements)

References 24 publications

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“…Because macitentan is an inhibitor of P‐gp in vitro , concurrent oral administration of both compounds could impair intestinal efflux of rivaroxaban into the gut lumen and thus accelerate its absorption and shorten t max . High rivaroxaban peak concentrations have been related to bleeding events , but the observed pharmacokinetic trend in this study was small and thus unlikely to be of clinical relevance, suggesting that, from a pharmacokinetic point of view, these drugs can probably be combined without dose adjustment. Moreover, the supposed mechanism of interaction suggests that this effect on absorption will be likely to be mitigated if macitentan is only administered after rivaroxaban C max is reached (i.e.…”

Section: Discussionmentioning

confidence: 71%

Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John's wort should be avoided

Huppertz

Werntz

Meid

et al. 2018

Brit J Clinical Pharma

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There is no evidence for a relevant pharmacokinetic interaction between macitentan and rivaroxaban suggesting that these two drugs can be combined without dose adjustment. SJW strongly increased CYP3A activity and substantially reduced rivaroxaban and macitentan exposure while estimated net endothelin antagonism only decreased by 20%, which is considered clinically irrelevant. The combination of SJW with rivaroxaban should be avoided.

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Section: Discussionmentioning

confidence: 71%

Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John's wort should be avoided

Huppertz

Werntz

Meid

et al. 2018

Brit J Clinical Pharma

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“…In the clinical pharmacology and biopharmaceutics review of the Food and Drug Administration, exponential relationships have been reported for both, AUC and C max , and the risk of major bleeding . In a recent analysis, higher rivaroxaban peak values (defined as anti‐Xa activity 3 h after drug intake), but not trough values (defined as predose anti‐Xa activity), were associated with major and nonmajor bleeding events . Thus, the increase in rivaroxaban AUC and C max caused by ciclosporin might be clinically relevant, despite an only modest increase in rivaroxaban AUC.…”

Section: Discussionmentioning

confidence: 99%

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

Brings

Lehmann

Foerster

et al. 2019

Brit J Clinical Pharma

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Aims: Rivaroxaban exposure is considerably increased by drugs that are combined P-glycoprotein (P-gp) and strong cytochrome P450 (CYP) 3A inhibitors (e.g. ketoconazole). The aim of the present study was to investigate the effects of the potent P-gp inhibitor ciclosporin and its combination with the moderate CYP3A inhibitor fluconazole on rivaroxaban pharmacokinetics and on CYP3A activity.Methods: Twelve healthy volunteers received 20 mg rivaroxaban orally alone, in combination with ciclosporin (dose-individualized oral regimen), and in combination with ciclosporin and fluconazole (400 mg day −1 orally). CYP3A4 activity was estimated using a midazolam microdose. Pharmacokinetics was analysed using noncompartmental and compartmental methods.Results: Compared to baseline, ciclosporin increased rivaroxaban average exposure by 47% (90% confidence interval 28-68%), maximum concentration by 104% (70-146%), and decreased CYP3A4 activity by 34% (25-42%). Ciclosporin combined with fluconazole increased rivaroxaban average exposure by 86% (58-119%) and maximum concentration by 115% (83-153%), which was considerably stronger than observed in historical controls receiving rivaroxaban with fluconazole alone, and decreased CYP3A4 activity by 79% (76-82%).Conclusion: Patients treated with rivaroxaban in combination with single modulators of multiple elimination pathways or multiple modulators of single elimination pathways (CYP3A, P-gp) require particular care. KEYWORDS ciclosporin, cytochrome P450 CYP3A, drug-drug interaction, fluconazole, midazolam, pharmacokinetics, rivaroxabanThe authors confirm that the PI for this paper is David Czock and that he had direct clinical responsibility for patients. Trial register: German clinical trials register.

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“…Rivaroxaban has been approved to be used clinically in the treatment of several thromboembolic disorders, such as prevention of venous thromboembolism after elective hip or knee replacement surgery . Since 2012, rivaroxaban has been used to prevent stroke among patients with nonvalvular atrial fibrillation in Japan …”

mentioning

confidence: 99%

“…7,8 Since 2012, rivaroxaban has been used to prevent stroke among patients with nonvalvular atrial fibrillation in Japan. 9 Rivaroxaban is a narrow-therapeutic-index (NTI) drug characterized by low within-subject variability as 1 of its noticeable properties. Otherwise, the patients will routinely experience toxicity and lack of efficacy.…”

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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Monitoring of anti-Xa activity and factors related to bleeding events: A study in Japanese patients with nonvalvular atrial fibrillation receiving rivaroxaban

Abstract: Peak AXA level was an independent predictor for bleeding events in Japanese NVAF patients receiving rivaroxaban.

Cited by 41 publications

References 24 publications

Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John's wort should be avoided

Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John's wort should be avoided

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

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

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