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Pharmacokinetics and drug interactions of direct oral anticoagulants

Pharmacokinetics and drug interactions of direct oral anticoagulants
Anticoagulant Bioavailability Metabolism and clearance* Half-life Potential for pharmacokinetic drug interactions*
Dabigatran
(Pradaxa)
  • 3 to 7% bioavailable
  • Unaffected by food
  • Capsule must be taken intact and requires gastric acidity for absorption
  • Over 80% cleared by the kidney
  • P-gp substrate*
  • 12 to 17 hours
  • Prolonged with kidney impairment and in older adults
  • P-gp inhibitors can increase dabigatran effect
  • P-gp inducers can decrease dabigatran effectΔ
  • Avoidance of some combinations or dose adjustment may be needed
Apixaban
(Eliquis)
  • 50% bioavailable
  • Unaffected by food
  • 27% cleared by the kidney
  • Metabolized, primarily by CYP3A4
  • P-gp substrate*
  • 12 hours
  • Prolonged in older adults
  • Strong dual CYP3A4 and P-gp inhibitors can increase apixaban effect
  • Strong CYP3A4 inducers and/or P-gp inducers can decrease apixaban effectΔ
  • Avoidance of some combinations or dose adjustment may be needed
Edoxaban
(Savaysa, Lixiana)
  • 62% bioavailable
  • Unaffected by food
  • 50% cleared by the kidney
  • Reduced efficacy in patients with nonvalvular atrial fibrillation and CrCl >95 mL/minute§
  • Undergoes minimal CYP metabolism
  • P-gp substrate*
  • 10 to 14 hours
  • Prolonged in renal impairment
  • P-gp inhibitors can increase edoxaban effect
  • P-gp inducers can decrease edoxaban effect
  • Avoidance of some combinations or dose adjustment may be needed
Rivaroxaban
(Xarelto)
  • 10 mg dose:
    • 80 to 100% bioavailable
    • Unaffected by food
  • 20 mg dose:
    • 66% bioavailable if taken when fasting; increased if taken with food
  • 36% cleared by the kidney
  • Metabolized, primarily by CYP3A4
  • P-gp substrate*
  • 5 to 9 hours
  • Prolonged to 11 to 13 hours in older adults
  • Strong dual CYP3A4 and P-gp inhibitors can increase rivaroxaban effect
  • Strong CYP3A4 inducers and/or P-gp inducers can decrease rivaroxaban effectΔ
  • Avoidance of some combinations or dose adjustment may be needed
Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with kidney impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate.

P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant.

* Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort. Refer to list available as a separate table in UpToDate.

¶ Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower DOAC levels, include carbamazepine, phenytoin, and rifampin. Refer to list available as a separate table in UpToDate.

Δ In patients with AF, combined use of levetiracetam or valproate with dabigatran, apixaban, or rivaroxaban was associated with an increased risk of ischemic stroke or systemic embolism. The mechanism of this interaction is unknown.[1]

◊ Inhibition of CYP3A4 (ie, without P-gp inhibition) may also increase apixaban and rivaroxaban effect, but to a lesser extent than dual inhibition of CYP3A4 and P-gp. Examples of CYP3A4 inhibitors that do not also inhibit P-gp include diltiazem, fluconazole, and voriconazole. Increased monitoring is advised.

§ Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information.
Reference:
  1. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic-interacting drugs and effectiveness and safety of direct acting oral anticoagulants: Nested case-control study. Clin Pharmacol Ther 2021; 110:1526.

Prepared with data from:

  1. Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved.
  2. Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed on December 9, 2021).
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