Edoxaban drug–drug interactions with ketoconazole, erythromycin, and cyclosporine

Abstract

AimsEdoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P‐glycoprotein (P‐gp). Three edoxaban drug–drug interaction studies examined the effects of P‐gp inhibitors with varying degrees of CYP3A4 inhibition.MethodsIn each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P‐gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study.ResultsCoadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half‐life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9‐fold and peak exposure by 8.7‐fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed.ConclusionsAdministration of dual inhibitors of P‐gp and CYP3A4 increased edoxaban exposure by less than two‐fold. This effect appears to be primarily due to inhibition of P‐gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.

Effect of the number of dose adjustment factors on bleeding risk in patients receiving 30 mg/day edoxaban

“…Further, the blood concentration of edoxaban in a ≤60 kg of body weight group was 1.8‐fold higher than that in the >60 kg group . Moreover, the AUC of edoxaban increased by 73% concomitant with the use of cyclosporine, which is a P‐gp inhibitor . High blood concentrations of edoxaban are also associated with an increased risk of bleeding .…”

Management of cancer-associated venous thromboembolism – a case-based practical approach

“…In general, moderate-to-strong inhibitors of P-gp and/ or CYP3A4 are assumed to increase DOAC plasma levels; thus, they at least theoretically confer an elevated risk of bleeding, whereas co-medications that induce P-gp and/ or CYP3A4 may lead to signifi cantly decreased DOAC plasma levels with insuffi cient protection against recurrent VTE (Table I) [44]. It has to mentioned, however, that most data on DOAC drug interactions have been derived from pharmacokinetic studies including healthy volunteers only, which renders the actual consequences of these drug interactions speculative [71][72][73][74]. Still, clinicians should be aware of certain co-medications or combinations thereof harbouring a potential for increasing the risk of bleeding or VTE recurrence, particularly in the presence of hepatic or renal failure or an advanced patient age.…”

Drug Interactions of New Oral Anticoagulants: Inside and Outside Table Cells

“…По мнению ав-торов исследования, ослабление эффекта взаимо-действия обусловлено тем, что верапамил при не-однократном назначении, наряду с ингибированием P-gp, индуцирует экспрессию P-gp в стенках кишечника [13]. Н 2 -блокаторы не влияют [10] не влияют [37] не влияют [36] Ингибиторы протонной помпы от -32% до -12,5% [11,38] не влияют [40] не влияют [41] Иммуносупрессанты Циклоспорин +73% [21] Противоопухолевые Бозутиниб не влияет [43] AUC -area under curve (площадь под кривой концентрация-время); НПВС -нестероидные противовоспалительные средства …”

“…В исследовании с участием здоровых добровольцев циклоспорин в однократной дозе 500 мг увеличивал AUC эдоксабана на 73% [21]. Влияние многократного приема циклоспорина на AUC эдоксабана, а также взаимодействие циклоспорина с другими НОАК в фармакокинетических исследованиях не изучалось.…”