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Review

Pharmacokinetics and pharmacodynamics of direct oral anticoagulants

, , & ORCID Icon
Pages 911-923 | Received 07 Jun 2023, Accepted 21 Nov 2023, Published online: 24 Nov 2023

References

  • Chen A, Stecker E, Warden BA. Direct oral anticoagulant use: a practical guide to common clinical challenges. J Am Heart Assoc. 2020;9. doi: 10.1161/JAHA.120.017559
  • DeHaas KA. The direct oral anticoagulants apixaban, rivaroxaban, and edoxaban. AmSoci Clin Lab Sci. 2017;30:2–6. doi: 10.29074/ascls.30.1.2
  • Byon W, Garonzik S, Boyd RA, et al. Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet. 2019;58(10):1265–1279. doi: 10.1007/s40262-019-00775-z
  • Bonar R, Favaloro EJ, Mohammed S, et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology. 2016;48(1):60–71. doi: 10.1016/j.pathol.2015.11.025
  • Bounameaux H, Camm AJ. Edoxaban: an update on the new oral direct factor Xa inhibitor. Drugs. 2014;74(11):1209–1231. doi: 10.1007/s40265-014-0261-1
  • Parasrampuria DA, Truitt KE. Pharmacokinetics and pharmacodynamics of edoxaban, a non-vitamin K antagonist oral anticoagulant that inhibits clotting factor Xa. Clin Pharmacokinet. 2016;55(6):641–655. doi: 10.1007/s40262-015-0342-7
  • Mueck W, Stampfuss J, Kubitza D, et al. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet. 2014;53(1):1–16. doi: 10.1007/s40262-013-0100-7
  • Graff J, von Hentig N, Misselwitz F, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on platelet-induced thrombin generation and prothrombinase activity 1. J Clin Pharmacol. 2007;47(11):1398–1407. doi: 10.1177/0091270007302952
  • Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47(1):47–59. doi: 10.2165/00003088-200847010-00005
  • Electronic Medicines Compendium. Pradaxa 150mg hard capsules [Internet]. 2022 [cited 2023 Jan 27]. Available from: https://www.medicines.org.uk/emc/product/4703/smpc.
  • Eisert WG, Hauel N, Stangier J, et al. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol. 2010;30(10):1885–1889. doi: 10.1161/ATVBAHA.110.203604
  • Mainbourg S, Cucherat M, Provencher S, et al. Twice- or once-daily dosing of direct oral anticoagulants, a systematic review and meta-analysis. Thromb Res. 2021 [cited 2023 Sep 12];197:24–32.
  • Jakowenko N, Nguyen S, Ruegger M, et al. Apixaban and rivaroxaban anti-Xa level utilization and associated bleeding events within an academic health system. Thromb Res. 2020;196:276–282. doi: 10.1016/j.thromres.2020.09.002
  • Rose DZ, Chang JY, Yi X, et al. Direct oral anticoagulant failures in atrial fibrillation with stroke: retrospective admission analysis and novel classification system. Neurohospitalist. 2023;13(3):256–265. doi: 10.1177/19418744231161390
  • Rose DZ, Burgin WS. Direct oral anticoagulant failure in stroke/transient ischaemic attack: neurologic and pharmacokinetic considerations. Eur Heart J Case Rep. 2020 [cited 2023 Sep 12];4:1–2. doi: 10.1093/ehjcr/ytaa178
  • Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330–1393. doi: 10.1093/eurheartj/ehy136
  • Margetić S, C¨elap I, Huzjan AL, et al. DOAC dipstick testing can reliably exclude the presence of clinically relevant DOAC concentrations in Circulation. Thromb Haemost. 2022 [cited 2023 May 23];122:1542–1548. doi: 10.1055/a-1753-2748
  • Merrelaar AE, Bögl MS, Buchtele N, et al. Performance of a qualitative point-of-care strip test to detect DOAC exposure at the emergency department: a cohort-type cross-sectional diagnostic accuracy study. Thromb Haemost. 2022 [cited 2023 May 23];122(10):1723–1731. doi: 10.1055/s-0042-1750327
  • Willekens G, Studt J, Mendez A, et al. A universal anti‐Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation. Br J Haematol. 2021;193(6):1203–1212. doi: 10.1111/bjh.17470
  • Samama M, Contant G, Spiro TE, et al. Laboratory assessment of rivaroxaban: a review. Thromb J. 2013;11(1):11. doi: 10.1186/1477-9560-11-11
  • Foulon-Pinto G, Lafuente C, Jourdi G, et al. Assessment of DOAC in GEriatrics (adage study): Rivaroxaban/apixaban concentrations and thrombin generation profiles in NVAF very elderly patients. Thromb Haemost. 2023 [cited 2023 May 23];123(4):402–414. doi: 10.1055/a-1981-1763
  • Douxfils J, Adcock DM, Bates SM, et al. 2021 update of the International council for standardization in haematology recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost. 2021;121(08):1008–1020. doi: 10.1055/a-1450-8178
  • Wang X, Mondal S, Wang J, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014;14(2):147–154. doi: 10.1007/s40256-013-0055-y
  • Daiichi Sankyo Europe GmbH. Lixiana summary of product characteristics [Internet]. 2020 [cited 2022 Dec 23]. Available from: https://www.ema.europa.eu/en/documents/product-information/lixiana-epar-product-information_en.pdf.
  • Electronic Medicines Compendium. Lixiana 60mg film-coated tablets [Internet]. 2022 [cited 2022 Dec 23]. Available from: https://www.medicines.org.uk/emc/product/6905/smpc#gref.
  • Ollier E, Hodin S, Lanoiselée J, et al. Effect of activated charcoal on rivaroxaban complex absorption. Clin Pharmacokinet. 2017;56(7):793–801. doi: 10.1007/s40262-016-0485-1
  • Alikhan R, Rayment R, Keeling D, et al. The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emer Med J. 2014;31(2):163–168. doi: 10.1136/emermed-2012-201976
  • Boehringer Ingelheim Pharmaceuticals Inc. Pradaxa prescribing infomation [Internet]. 2011 [cited 2023 Jan 27]. Ava: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022512s007lbl.pdf.
  • Boehringer Ingelheim International GmbH. Pradaxa summary of product characteristics [Internet]. 2018 [cited 2023 Jan 27]. Available from: https://www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product-information_en.pdf.
  • Electronic Medicines Compendium. Ondexxya 200 mg powder for solution for infusion [Internet]. 2022 [cited 2022 Dec 12]. Available from: https://www.medicines.org.uk/emc/product/10933/smpc.
  • Electronic Medicines Compendium. Praxbind 2.5 g/50 mL solution for injection/infusion [Internet]. 2022 [cited 2023 Feb 3]. Available from: https://www.medicines.org.uk/emc/product/5073.
  • Alexion Europe SAS. Ondexxya summary of product characterisitcs [Internet]. 2021 [cited 2023 Feb 10]. Available from: https://www.ema.europa.eu/en/documents/product-information/ondexxya-epar-product-information_en.pdf.
  • Alexion Pharmaceuticals Inc. Andexxa prescribing information [Internet]. 2022 [cited 2023 Feb 10]. Available from: https://www.fda.gov/media/113279/download.
  • Benz AP, Xu L, Eikelboom JW, et al. Andexanet alfa for specific anticoagulation reversal in patients with acute bleeding during treatment with edoxaban. Thromb Haemost. 2022;122:998–1005.
  • National Institute of Health. Trial of andexanet alfa in ICH patients receiving an oral FXa inhibitor [Internet]. 2023 [cited 2023 Feb 10]. Available from: https://clinicaltrials.gov/ct2/show/NCT03661528.
  • Müller M, Eastline J, Nagler M, et al. Application of prothrombin complex concentrate for reversal of direct oral anticoagulants in clinical practice: indications, patient characteristics and clinical outcomes compared to reversal of vitamin K antagonists. Scand J Trauma Resusc Emerg Med. 2019 [cited 2023 Sep 12];27. PMC6480883/. doi: 10.1186/s13049-019-0625-3
  • Amin S, Kasischke KA, Elsayed K, et al. No time to lose: cases of anticoagulant reversal before Thrombolysis in acute ischemic stroke patients. Cureus. 2022 [cited 2023 Sep 12];14. doi: 10.7759/cureus.21406
  • Byon W, Nepal S, Schuster AE, et al. Regional gastrointestinal absorption of apixaban in healthy subjects. J Clin Pharmacol. 2018;58(7):965–971. doi: 10.1002/jcph.1097
  • Vakkalagadda B, Frost C, Byon W, et al. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa. Am J Cardiovasc Drugs. 2016;16(2):119–127. doi: 10.1007/s40256-015-0157-9
  • Song Y, Chang M, Suzuki A, et al. Evaluation of crushed tablet for oral administration and the Effect of food on apixaban pharmacokinetics in healthy adults. Clin Ther. 2016;38(7):1674–1685.e1. doi: 10.1016/j.clinthera.2016.05.004
  • Frost C, Wang J, Nepal S, et al. Apixaban, an oral, direct factor X a inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol. 2013;75:476–487.
  • Electronic Medicines Compendium. Eliquis 5 mg film-coated tablets [Internet]. 2022 [cited 2022 Dec 12]. Available from: https://www.medicines.org.uk/emc/product/2878/smpc.
  • Bristol-Myers Squibb/Pfizer EEIG. Eliquis summary of product characteristics [Internet]. 2021 [cited 2022 Dec 23]. Available from: https://www.ema.europa.eu/en/documents/product-information/eliquis-epar-product-information_en.pdf.
  • Bristol-Myers Squibb Company PI. Eliquis (apixaban) prescribing information. [Internet]. 2021 [cited 2022 Dec 12]. Available from: https://packageinserts.bms.com/pi/pi_eliquis.pdf.
  • Frost C, Nepal S, Wang J, et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor X a inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013;76:776–786.
  • Song Y, Wang X, Perlstein I, et al. Relative bioavailability of apixaban solution or crushed tablet formulations administered by mouth or nasogastric tube in healthy subjects. Clin Ther. 2015;37(8):1703–1712. doi: 10.1016/j.clinthera.2015.05.497
  • Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol. 2013;76:908–916. doi: 10.1111/bcp.12114
  • Choi Y, Kushnir M, Billett HH. Apixaban is safe and effective in morbidly obese patients: a retrospective analysis of 390 patients with BMI ≥40. Blood. 2017;130:1105. doi: 10.1182/blood.V130.Suppl_1.1105.1105
  • Cohen A, Sah J, Lee T, et al. Effectiveness and safety of apixaban vs. Warfarin in venous thromboembolism patients with obesity and morbid obesity. J Clin Med. 2021;10(2):200. doi: 10.3390/jcm10020200
  • Cohen AT, Pan S, Byon W, et al. Efficacy, safety, and exposure of apixaban in patients with high body weight or obesity and venous thromboembolism: insights from AMPLIFY. Adv Ther. 2021;38(6):3003–3018. doi: 10.1007/s12325-021-01716-8
  • O’Kane CP, Avalon JCO, Lacoste JL, et al. Apixaban and rivaroxaban use for atrial fibrillation in patients with obesity and BMI ≥50 kg/m 2. Pharmacother J Human Pharmacol Drug Ther. 2022;42(2):112–118. doi: 10.1002/phar.2651
  • Ballerie A, Nguyen Van R, Lacut K, et al. Apixaban and rivaroxaban in obese patients treated for venous thromboembolism: drug levels and clinical outcomes. Thromb Res. 2021;208:39–44. doi: 10.1016/j.thromres.2021.10.009
  • Jamieson MJ, Byon W, Dettloff RW, et al. Apixaban use in obese patients: a review of the pharmacokinetic, Interventional, and observational study data. Am J Cardiovasc Drugs. 2022;22(6):615–631. doi: 10.1007/s40256-022-00524-x
  • He K, Luettgen JM, Zhang D, et al. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor. Eur J Drug Metab Pharmacokinet. 2011;36(3):129–139. doi: 10.1007/s13318-011-0037-x
  • Frost CE, Song Y, Shenker A, et al. Effects of age and sex on the single-dose pharmacokinetics and pharmacodynamics of apixaban. Clin Pharmacokinet. 2015;54(6):651–662. doi: 10.1007/s40262-014-0228-0
  • Cirincione B, Kowalski K, Nielsen J, et al. Population pharmacokinetics of apixaban in subjects with nonvalvular atrial fibrillation. CPT Pharmacometrics Syst Pharmacol. 2018;7(11):728–738. doi: 10.1002/psp4.12347
  • Wang L, Zhang D, Raghavan N, et al. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos. 2010;38(3):448–458. doi: 10.1124/dmd.109.029694
  • Zhang D, He K, Herbst JJ, et al. Characterization of Efflux Transporters involved in distribution and disposition of apixaban. Drug Metab Dispos. 2013;41(4):827–835. doi: 10.1124/dmd.112.050260
  • Fernandez S, Lenoir C, Samer C, et al. Drug interactions with apixaban: a systematic review of the literature and an analysis of VigiBase, the World Health Organization database of spontaneous safety reports. Pharmacol Res Perspect. 2020;8(5):8. doi: 10.1002/prp2.647
  • Candeloro M, Eikelboom JW, Chan N, et al. Carbamazepine, phenytoin, and oral anticoagulants: drug‐drug interaction and clinical events in a retrospective cohort. Res Pract Thromb Haemost. 2022;6(2):6. doi: 10.1002/rth2.12650
  • Shurrab M, Jackevicius CA, Austin PC, et al. Association between concurrent use of amiodarone and DOACs and risk of bleeding in patients with atrial fibrillation. Am J Cardiol. 2023 [cited 2023 Sep 12];186:58–65.
  • Lin SY, Bin LY, Ho LT, et al. Impact of amiodarone on plasma concentration of direct oral anticoagulant in patients with atrial fibrillation. J Formos Med Assoc. 2023 [cited 2023 Sep 12];122(8):776–784. doi: 10.1016/j.jfma.2023.02.012
  • U.S. Food and Drug Administration. FDA’s Examples of Drugs that Interact with CYP Enzymes and Transporter Systems. 2023.
  • Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1):74–81. doi: 10.1124/dmd.108.023143
  • Fawzy AM, Lip GYH. Pharmacokinetics and pharmacodynamics of oral anticoagulants used in atrial fibrillation. Expert Opin Drug Metab Toxicol. 2019;15(5):381–398. doi: 10.1080/17425255.2019.1604686
  • Chang M, Yu Z, Shenker A, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol. 2016;56(5):637–645. doi: 10.1002/jcph.633
  • Byon W, Sweeney K, Frost C, et al. Population pharmacokinetics, pharmacodynamics, and exploratory exposure-response analyses of apixaban in subjects treated for venous thromboembolism. CPT Pharmacometrics Syst Pharmacol. 2017;6:340–349. doi: 10.1002/psp4.12184
  • Siontis KC, Zhang X, Eckard A, et al. Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States. Circulation. 2018;138(15):1519–1529. doi: 10.1161/CIRCULATIONAHA.118.035418
  • Stanifer JW, Pokorney SD, Chertow GM, et al. Apixaban versus warfarin in patients with atrial fibrillation and advanced chronic kidney disease. Circulation. 2020;141(17):1384–1392. doi: 10.1161/CIRCULATIONAHA.119.044059
  • Chen C, Cao Y, Zheng Y, et al. Effect of rivaroxaban or apixaban in atrial fibrillation patients with stage 4–5 chronic kidney disease or on dialysis. Cardiovasc Drugs Ther. 2021;35(2):273–281. doi: 10.1007/s10557-021-07144-8
  • Cohen AT, Sah J, Dhamane AD, et al. Effectiveness and safety of apixaban versus warfarin in venous thromboembolism patients with chronic kidney disease. Thromb Haemost. 2022;122(6):926–938. doi: 10.1055/s-0041-1740254
  • Gurevitz C, Giladi E, Barsheshet A, et al. Comparison of low and Full dose apixaban versus warfarin in patients with atrial fibrillation and renal dysfunction (from a national registry). Am J Cardiol. 2021;159:87–93. doi: 10.1016/j.amjcard.2021.08.022
  • Knueppel P, Bang SH, Troyer C, et al. Evaluation of standard versus reduced dose apixaban for the treatment of venous thromboembolism in patients with severe renal disease (ESRD-VTE). Thromb Res. 2022;220:91–96. doi: 10.1016/j.thromres.2022.10.014
  • Harrington J, Carnicelli AP, Hua K, et al. Direct oral anticoagulants versus warfarin across the spectrum of kidney function: patient-level network meta-analyses from COMBINE AF. Circulation. 2023 [cited 2023 Sep 12];147(23):1748–1757. doi: 10.1161/CIRCULATIONAHA.122.062752
  • Parasrampuria DA, Kanamaru T, Connor A, et al. Evaluation of regional gastrointestinal absorption of edoxaban using the enterion capsule. J Clin Pharmacol. 2015;55(11):1286–1292. doi: 10.1002/jcph.540
  • Yin OQP, Tetsuya K, Miller R. Edoxaban population pharmacokinetics and exposure–response analysis in patients with non-valvular atrial fibrillation. Eur J Clin Pharmacol. 2014;70(11):1339–1351. doi: 10.1007/s00228-014-1736-4
  • Matsushima N, Lee F, Sato T, et al. Bioavailability and safety of the factor Xa inhibitor edoxaban and the effects of quinidine in healthy subjects. Clin Pharmacol Drug Dev. 2013;2(4):358–366. doi: 10.1002/cpdd.53
  • Liu L, Li X, Liu Y, et al. Bioequivalence and pharmacokinetic study of 2 edoxaban tablets in healthy Chinese subjects. Clin Pharmacol Drug Dev. 2022;11(12):1440–1446. doi: 10.1002/cpdd.1156
  • Mendell J, Tachibana M, Shi M, et al. Effects of food on the pharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers. J Clin Pharmacol. 2011;51(5):687–694. doi: 10.1177/0091270010370974
  • Daiichi Sankyo Co. L. Edoxaban (Savaysa) prescribing information [Internet]. 2015 [cited 2022 Dec 23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf.
  • Duchin K, Duggal A, Atiee GJ, et al. An open-label crossover study of the pharmacokinetics of the 60-mg edoxaban tablet crushed and administered either by a nasogastric tube or in apple puree in healthy adults. Clin Pharmacokinet. 2018;57(2):221–228. doi: 10.1007/s40262-017-0554-0
  • Moll S, Crona DJ, Martin K. Direct oral anticoagulants in extremely obese patients: OK to use? Res Pract Thromb Haemost. 2019;3(2):152–155. doi: 10.1002/rth2.12178
  • Yin OQP, Miller R. Population pharmacokinetics and dose–exposure proportionality of edoxaban in healthy volunteers. Clin Drug Investig. 2014;34(10):743–752. doi: 10.1007/s40261-014-0229-7
  • Martin KA, Beyer‐Westendorf J, Davidson BL, et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: updated communication from the ISTH SSC subcommittee on control of anticoagulation. J Thromb Haemost. 2021;19(8):1874–1882. doi: 10.1111/jth.15358
  • Boriani G, Ruff CT, Kuder JF, et al. Edoxaban versus warfarin in patients with atrial fibrillation at the extremes of body weight: an analysis from the ENGAGE AF-TIMI 48 trial. Thromb Haemost. 2021;121(2):140–149. doi: 10.1055/s-0040-1716540
  • Krekels EHJ, Niebecker R, Karlsson MO, et al. Population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation in the ENGAGE AF-TIMI 48 study, a phase III clinical trial. Clin Pharmacokinet. 2016;55(9):1079–1090. doi: 10.1007/s40262-016-0378-3
  • Bathala MS, Masumoto H, Oguma T, et al. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in Humans. Drug Metab Dispos. 2012;40(12):2250–2255. doi: 10.1124/dmd.112.046888
  • Mikkaichi T, Yoshigae Y, Masumoto H, et al. Edoxaban Transport via P-Glycoprotein is a key factor for the drug’s disposition. Drug Metab Dispos. 2014;42(4):520–528. doi: 10.1124/dmd.113.054866
  • Mendell J, Johnson L, Chen S. An open-label, phase 1 study to evaluate the effects of hepatic impairment on edoxaban pharmacokinetics and pharmacodynamics. J Clin Pharmacol. 2015;55(12):1395–1405. doi: 10.1002/jcph.550
  • Jönsson S, Simonsson USH, Miller R, et al. Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study. J Clin Pharmacol. 2015;55(11):1268–1279. doi: 10.1002/jcph.541
  • Shimizu T, Tachibana M, Kimura T, et al. Population pharmacokinetics of edoxaban in Japanese atrial fibrillation patients with severe renal impairment. Clin Pharmacol Drug Dev. 2017;6(5):484–491. doi: 10.1002/cpdd.329
  • Lip GYH, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J. 2014;35(28):1844–1855. doi: 10.1093/eurheartj/ehu181
  • Ono R, Nishimura K, Takahashi H, et al. Impact of renal function on anti-factor Xa activity concentrations with edoxaban use in patients with non-valvular atrial fibrillation. Drugs R D. 2022;22(4):281–288. doi: 10.1007/s40268-022-00403-5
  • Yu HT, Yang P-S, Kim T-H, et al. Impact of renal function on outcomes with edoxaban in real-world patients with atrial fibrillation. Stroke. 2018;49(10):2421–2429. doi: 10.1161/STROKEAHA.118.021387
  • Fazio G, Dentamaro I, Gambacurta R, et al. Safety of edoxaban 30 mg in elderly patients with severe renal impairment. Clin Drug Investig. 2018;38(11):1023–1030. doi: 10.1007/s40261-018-0693-6
  • Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406–1415.
  • Bohula EA, Giugliano RP, Ruff CT, et al. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial. Circulation. 2016;134(1):24–36. doi: 10.1161/CIRCULATIONAHA.116.022361
  • Hakeam HA, Al-Sanea N. Effect of major gastrointestinal tract surgery on the absorption and efficacy of direct acting oral anticoagulants (DOACs). J Thromb Thrombolysis. 2017;43(3):343–351. doi: 10.1007/s11239-016-1465-x
  • Bratsos S. Pharmacokinetic properties of rivaroxaban in healthy human subjects. Cureus. 2019. doi: 10.7759/cureus.5484
  • Stampfuss J, Kubitza D, Becka M, et al. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther. 2013;51(7):549–561. doi: 10.5414/CP201812
  • Janssen Pharmaceuticals. XARELTO (rivaroxaban) [Internet]. 2014 [cited 2023 Jan 13]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022406s015lbl.pdf.
  • Electronic Medicines Compendium. Xarelto 15mg & 20mg film-coated tablets treatment initiation pack [Internet]. 2022 [cited 2023 Jan 13]. Available from: https://www.medicines.org.uk/emc/product/8419/smpc#gref.
  • Electronic Medicines Compendium. Xarelto 10 mg film-coated tablets [Internet]. 2022 [cited 2023 Jan 13]. Available from: https://www.medicines.org.uk/emc/product/6402/smpc.
  • Bayer AG Xarelto summary of product characteristics. 2018 [cited 2023 Jan 13]. Available from: https://www.ema.europa.eu/en/documents/product-information/xarelto-epar-product-information_en.pdf.
  • Moore KT, Krook MA, Vaidyanathan S, et al. Rivaroxaban crushed tablet suspension characteristics and relative bioavailability in healthy adults when administered orally or via nasogastric tube. Clin Pharmacol Drug Dev. 2014;3(4):321–327. doi: 10.1002/cpdd.123
  • Ashton V, Mudarris L, Moore KT. The pharmacology, efficacy, and safety of rivaroxaban in obese patient populations. Am J Cardiovasc Drugs. 2021;21(3):283–297. doi: 10.1007/s40256-020-00434-w
  • Kubitza D, Becka M, Zuehlsdorf M, et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007;47(2):218–226. doi: 10.1177/0091270006296058
  • Kubitza D, Becka M, Roth A, et al. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban-an oral, direct factor Xa inhibitor. J Clin Pharmacol. 2013;53:249–255. doi: 10.1002/jcph.5
  • Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76(3):455–466. doi: 10.1111/bcp.12075
  • Ngo LT, Yang S, Tran QT, et al. Effects of carbamazepine and phenytoin on pharmacokinetics and pharmacodynamics of rivaroxaban. Pharmaceutics. 2020;12(11):1040. doi: 10.3390/pharmaceutics12111040
  • Kubitza D, Roth A, Becka M, et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2013;76(1):89–98. doi: 10.1111/bcp.12054
  • Qamar A, Vaduganathan M, Greenberger NJ, et al. Oral anticoagulation in patients with liver disease. J Am Coll Cardiol. 2018;71(19):2162–2175. doi: 10.1016/j.jacc.2018.03.023
  • Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5):703–712. doi: 10.1111/j.1365-2125.2010.03753.x
  • Ashton V, Kerolus‐Georgi S, Moore KT. The pharmacology, efficacy, and safety of rivaroxaban in renally impaired patient populations. J Clin Pharmacol. 2021;61(8):1010–1026. doi: 10.1002/jcph.1838
  • Moj D, Maas H, Schaeftlein A, et al. A comprehensive whole-body physiologically based pharmacokinetic model of dabigatran etexilate, dabigatran and dabigatran glucuronide in healthy adults and renally impaired patients. Clin Pharmacokinet. 2019;58(12):1577–1593. doi: 10.1007/s40262-019-00776-y
  • Grainger B, Holloway R, Merriman E, et al. Evidence of impaired dabigatran absorption following laparoscopic Roux‐en‐Y gastric bypass surgery: the Auckland regional experience (2011–2018). Br J Haematol. 2020;191: doi: 10.1111/bjh.17004
  • Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin App Thrombosis/Hemostasis. 2009;15:9S–16S. doi: 10.1177/1076029609343004
  • Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol. 2005;45(5):555–565. doi: 10.1177/0091270005274550
  • Stangier J, Rathgen K, Stähle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303. doi: 10.1111/j.1365-2125.2007.02899.x
  • Piran S, Traquair H, Chan N, et al. Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: a retrospective study. Res Pract Thromb Haemost. 2018;2(4):684–688. doi: 10.1002/rth2.12146
  • Jacobs M, Ezekowitz M, Nagarakanti R, et al. Body mass index from the RE-LY trial: further evidence of the obesity paradox. Eur Heart J. 2022;43(Supplement_2):43. doi: 10.1093/eurheartj/ehac544.629
  • Coates J, Bitton E, Hendje A, et al. Clinical outcomes of dabigatran use in patients with non-valvular atrial fibrillation and weight >120 kg. Thromb Res. 2021;208:176–180. doi: 10.1016/j.thromres.2021.11.007
  • Steffel J, Collins R, Antz M, et al. 2021 European Heart rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. EP Europace. 2021;23:1612–1676. doi: 10.1093/europace/euab065
  • Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in Humans. Drug Metab Dispos. 2008;36(2):386–399. doi: 10.1124/dmd.107.019083
  • Ebner T, Wagner K, Wienen W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: In Vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010;38(9):1567–1575. doi: 10.1124/dmd.110.033696
  • Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48(12):1411–1419. doi: 10.1177/0091270008324179
  • Stangier J, Rathgen K, Stähle H, et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate. Clin Pharmacokinet. 2010;49(4):259–268. doi: 10.2165/11318170-000000000-00000
  • Skripka A, Sychev D, Bochkov P, et al. Factors affecting trough plasma dabigatran concentrations in patients with atrial fibrillation and chronic kidney disease. High Blood Pressure Cardiovasc Prev. 2020;27(2):151–156. doi: 10.1007/s40292-020-00373-2
  • Medicines and Healthcare Products Regulatory Agency. Prescribing medicines in renal impairment: using the appropriate estimate of renal function to avoid the risk of adverse drug reactions [Internet]. 2019 [cited 2022 Dec 12]. Available from: https://www.gov.uk/drug-safety-update/prescribing-medicines-in-renal-impairment-using-the-appropriate-estimate-of-renal-function-to-avoid-the-risk-of-adverse-drug-reactions.
  • MacCallum PK, Mathur R, Hull SA, et al. Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention in atrial fibrillation: a cross-sectional study. BMJ Open. 2013;3(9):e003343. doi: 10.1136/bmjopen-2013-003343
  • NHS North West Coast Strategic Networks. Consensus statement on how to calculate the creatinine clearance (CrCl) which is necessary when assessing the dose of direct-acting oral anticoagulants (DOACs) [Internet]. 2018 [cited 2022 Dec 12]. Available from: https://www.england.nhs.uk/north/wp-content/uploads/sites/5/2019/01/consensus-statement-on-CrCl-calculation-for-DOACs-final.pdf.
  • Fanikos J, Burnett AE, Mahan CE, et al. Renal function and direct oral anticoagulant treatment for venous thromboembolism. Am J Med. 2017;130(10):1137–1143. doi: 10.1016/j.amjmed.2017.06.004
  • Fanikos J, Burnett AE, Mahan CE, et al. Renal function considerations for stroke prevention in atrial fibrillation. Am J Med. 2017;130(9):1015–1023. doi: 10.1016/j.amjmed.2017.04.015
  • Schwartz JB. Potential Effect of Substituting Estimated Glomerular Filtration Rate for Estimated Creatinine Clearance for Dosing of Direct Oral Anticoagulants. J Am Geriatr Soc. 2016;64(10):1996–2002. doi: 10.1111/jgs.14288
  • Martin K, Beyer‐Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308–1313. doi: 10.1111/jth.13323
  • Harkness W, Pipitone O, Joss J, et al. Observed Apixaban Anti-Xa Levels in Obese Patients. Ann Pharmacother. 2022 [cited 2023 Sep 12];56(11):1215–1221. doi: 10.1177/10600280221077158
  • Martin KA, Lancki N, Li C, et al. DOAC compared with warfarin for VTE in patients with obesity: a retrospective cohort study conducted through the VENUS network. J Thromb Thrombolysis. 2023 [cited 2023 Sep 12];55(4):685–690. doi: 10.1007/s11239-023-02774-1
  • Barakat AF, Jain S, Masri A, et al. Outcomes of direct oral anticoagulants in atrial fibrillation patients across different body mass index categories. JACC Clin Electrophysiol. 2021;7(5):649–658. doi: 10.1016/j.jacep.2021.02.002