The Effect of Rifampin on the Pharmacokinetics of Edoxaban in Healthy Adults

Abstract

Background and ObjectiveThe oral direct factor Xa inhibitor edoxaban is a P-glycoprotein (P-gp) substrate metabolized via carboxylesterase-1 and cytochrome P450 (CYP) 3A4/5. The effect of rifampin-induced induction of P-gp and CYP3A4/5 on transport and metabolism of edoxaban through the CYP3A4/5 pathway was investigated in a single-dose edoxaban study.MethodsThis was a phase 1, open-label, two-treatment, two-period, single-sequence drug interaction study in healthy adults. All subjects received a single oral 60 mg edoxaban dose in period 1, and 7 days of 600 mg rifampin (2 × 300 mg capsules once daily) with a single oral edoxaban 60 mg dose administered concomitantly on day 7 in period 2. A 6-day washout period separated the treatments. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of pharmacodynamic markers of coagulation were performed.ResultsIn total, 34 healthy subjects were enrolled; 32 completed the study. Coadministration of rifampin with edoxaban decreased edoxaban exposure but increased active metabolite exposure. Rifampin increased apparent oral clearance of edoxaban by 33 % and decreased its half-life by 50 %. Anticoagulant effects based on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) with and without rifampin at early time points were maintained to a greater-than-expected degree than with edoxaban exposure alone, presumably because of an increased contribution from the active metabolites. Edoxaban was well tolerated in this healthy adult population.ConclusionsRifampin reduced exposure to edoxaban while increasing exposure to its active metabolites M4 and M6. PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.

Direct oral anticoagulants: Current indications and unmet needs in the treatment of venous thromboembolism

“…As DOACs are substrates of P-gp and CYP3A, there are exposed to potential drug-drug interactions with strong P-gp/CYP3A inhibitors or inducers [2,3,[17][18][19][20][21]. Table 1 summarizes the known effects of such drugs on DAOC exposure.…”

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

“…Показатели снижения плазменных кон-центраций НОАК под влиянием рифампицина получены в исследованиях с участием здоровых добровольцев при его назначении в дозе 600 мг/сут [23][24][25][26]. В ев-ропейской таблице эти показатели приведены дважды.…”

Factor Xa Inhibitors

“…3.4) is a potent, highly selective factor Xa inhibitor with a high affinity for free factor Xa (K i 0.56 nM) and for factor Xa bound to the prothrombinase complex (K i 2.98 nM) [40]. It has predictable and consistent pharmacokinetics with dose proportional increases in plasma concentrations, and a half-life of approximately 10-14 h [10,41,42]. Additionally, edoxaban has a rapid onset of action and high oral bioavailability (61.8 %), reaching maximum plasma concentrations 1-2 h after administration, and inhibition of thrombin formation over ~24 h, supporting once-daily dosing [10,12,43].…”