Skip to main content

Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care

Abstract

Factor Xa-inhibitor apixaban is an oral anticoagulant prescribed in atrial fibrillation (AF) for stroke prevention. Its pharmacokinetic profile is known to be affected by cytochrome P450 (CYP)3A metabolism, while it is also a substrate of the efflux transporters ATP-binding cassette (ABC)B1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein, BCRP). In this study, we assessed the impact of interacting medication and pharmacogenetic variation to better explain apixaban concentration differences among 358 Caucasian AF patients. Genotyping (ABCG2, ABCB1, CYP3A4*22, CYP3A5*3) was performed by TaqMan assays, and apixaban quantified by mass spectrometry. The typical patient was on average 77.2 years old, 85.5 kg, and had a serum creatinine of 103.1 µmol/L. Concomitant amiodarone, an antiarrhythmic agent and moderate CYP3A/ABCB1 inhibitor, the impaired-function variant ABCG2 c.421C > A, and sex predicted higher apixaban concentrations when controlling for age, weight and serum creatinine (multivariate regression; R2 = 0.34). Our findings suggest that amiodarone and ABCG2 genotype contribute to interpatient apixaban variability beyond known clinical factors.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. Byon W, Garonzik S, Boyd RA, Frost CE (2019) Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet. https://doi.org/10.1007/s40262-019-00775-z

    Article  PubMed  PubMed Central  Google Scholar 

  2. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:981–992. https://doi.org/10.1056/NEJMoa1107039

    CAS  Article  PubMed  Google Scholar 

  3. Connolly SJ, Eikelboom J, Joyner C, Diener H-C, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim K-H, Lewis BS, Van Mieghem W, Lip GYH, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S (2011) Apixaban in patients with atrial fibrillation. N Engl J Med 364:806–817. https://doi.org/10.1056/NEJMoa1007432

    CAS  Article  PubMed  Google Scholar 

  4. Barnes GD, Lucas E, Alexander GC, Goldberger ZD (2015) National trends in ambulatory oral anticoagulant use. Am J Med 128:1300-5 e2. https://doi.org/10.1016/j.amjmed.2015.05.044

    Article  PubMed  Google Scholar 

  5. Gulilat M, Tang A, Gryn SE, Leong-Sit P, Skanes AC, Alfonsi JE, Dresser GK, Henderson SL, Rose RV, Lizotte DJ, Teft WA, Schwarz UI, Tirona RG, Kim RB (2017) Interpatient variation in Rivaroxaban and Apixaban plasma concentrations in routine care. Can J Cardiol 33:1036–1043. https://doi.org/10.1016/j.cjca.2017.04.008

    Article  PubMed  Google Scholar 

  6. Upreti VV, Wang J, Barrett YC, Byon W, Boyd RA, Pursley J, LaCreta FP, Frost CE (2013) Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol 76:908–916. https://doi.org/10.1111/bcp.12114

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, Yu Z, Shenker A, Barrett YC, Mosqueda-Garcia R, Lacreta F (2013) Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 76:776–786. https://doi.org/10.1111/bcp.12106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Frost C, Wang J, Nepal S, Schuster A, Barrett YC, Mosqueda-Garcia R, Reeves RA, LaCreta F (2013) Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 75:476–487. https://doi.org/10.1111/j.1365-2125.2012.04369.x

    CAS  Article  PubMed  Google Scholar 

  9. Bhagirath VC, Eikelboom JW, Hirsh J, Coppens M, Ginsberg J, Vanassche T, Yuan F, Chan N, Yusuf S, Connolly SJ (2017) Apixaban-calibrated anti-FXa activity in relation to outcome events and clinical characteristics in patients with atrial fibrillation: results from the AVERROES trial. TH Open 1:e139–e145

    Article  PubMed  PubMed Central  Google Scholar 

  10. Testa S, Legnani C, Antonucci E, Paoletti O, Dellanoce C, Cosmi B, Pengo V, Poli D, Morandini R, Testa R, Tripodi A, Palareti G, Coordinator of SR (2019) Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost. https://doi.org/10.1111/jth.14457

    Article  PubMed  PubMed Central  Google Scholar 

  11. Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, Pinto D, Chen S, Bonacorsi S, Wong PC, Zhang D (2009) Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 37:74–81. https://doi.org/10.1124/dmd.108.023143

    CAS  Article  PubMed  Google Scholar 

  12. Wang L, Zhang D, Raghavan N, Yao M, Ma L, Frost CA, Maxwell BD, Chen S-y, He K, Goosen TC (2010) In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos 38:448–458

    CAS  Article  PubMed  Google Scholar 

  13. Zhang D, Frost CE, He K, Rodrigues AD, Wang X, Wang L, Goosen TC, Humphreys WG (2013) Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. Drug Metab Dispos 41:906–915. https://doi.org/10.1124/dmd.112.050575

    CAS  Article  PubMed  Google Scholar 

  14. Zhang D, He K, Herbst JJ, Kolb J, Shou W, Wang L, Balimane PV, Han YH, Gan J, Frost CE, Humphreys WG (2013) Characterization of efflux transporters involved in distribution and disposition of apixaban. Drug Metab Dispos 41:827–835. https://doi.org/10.1124/dmd.112.050260

    CAS  Article  PubMed  Google Scholar 

  15. Voukalis C, Lip GY, Shantsila E (2016) Drug-drug interactions of non-vitamin K oral anticoagulants. Expert Opin Drug Metab Toxicol 12:1445–1461. https://doi.org/10.1080/17425255.2016.1225037

    CAS  Article  PubMed  Google Scholar 

  16. Frost CE, Byon W, Song Y, Wang J, Schuster AE, Boyd RA, Zhang D, Yu Z, Dias C, Shenker A, LaCreta F (2015) Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol 79:838–846. https://doi.org/10.1111/bcp.12541

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Bashir B, Stickle DF, Chervoneva I, Kraft WK (2018) Drug-drug interaction study of Apixaban with cyclosporine and tacrolimus in healthy volunteers. Clin Transl Sci 11:590–596. https://doi.org/10.1111/cts.12580

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D, Yu Z, Dias C, Shenker A, LaCreta F (2016) Effect of Rifampin on the pharmacokinetics of Apixaban, an oral direct inhibitor of factor Xa. Am J Cardiovasc Drugs 16:119–127. https://doi.org/10.1007/s40256-015-0157-9

    CAS  Article  PubMed  Google Scholar 

  19. Eliquis® (apixaban) 2.5 mg and 5 mg product monograph. Bristol-Myers Squibb. 2018

  20. Frost CE, Song Y, Shenker A, Wang J, Barrett YC, Schuster A, Harris SI, LaCreta F (2015) Effects of age and sex on the single-dose pharmacokinetics and pharmacodynamics of apixaban. Clin Pharmacokinet 54:651–662. https://doi.org/10.1007/s40262-014-0228-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Cirincione B, Kowalski K, Nielsen J, Roy A, Thanneer N, Byon W, Boyd R, Wang X, Leil T, LaCreta F, Ueno T, Oishi M, Frost C (2018) Population pharmacokinetics of Apixaban in subjects with nonvalvular atrial fibrillation. CPT Pharm Syst Pharmacol 7:728–738. https://doi.org/10.1002/psp4.12347

    CAS  Article  Google Scholar 

  22. Tirona RG, Kassam Z, Strapp R, Ramu M, Zhu C, Liu M, Schwarz UI, Kim RB, Al-Judaibi B, Beaton MD (2018) Apixaban and Rosuvas–tatin pharmacokinetics in nonalcoholic fatty liver disease. Drug Metab Dispos 46:485–492. https://doi.org/10.1124/dmd.117.079624

    CAS  Article  PubMed  Google Scholar 

  23. Chang M, Yu Z, Shenker A, Wang J, Pursley J, Byon W, Boyd RA, LaCreta F, Frost CE (2016) Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol 56:637–645. https://doi.org/10.1002/jcph.633

    CAS  Article  PubMed  Google Scholar 

  24. Rottenstreich A, Zacks N, Kleinstern G, Raccah BH, Roth B, Da’as N, Kalish Y (2018) Direct-acting oral anticoagulant drug level monitoring in clinical patient management. J Thromb Thrombolysis. https://doi.org/10.1007/s11239-018-1643-0

    Article  PubMed  Google Scholar 

  25. DeGorter MK, Xia CQ, Yang JJ, Kim RB (2012) Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol 52:249–273. https://doi.org/10.1146/annurev-pharmtox-010611-134529

    CAS  Article  PubMed  Google Scholar 

  26. Kondo C, Suzuki H, Itoda M, Ozawa S, Sawada J, Kobayashi D, Ieiri I, Mine K, Ohtsubo K, Sugiyama Y (2004) Functional analysis of SNPs variants of BCRP/ABCG2. Pharm Res 21:1895–1903

    CAS  Article  PubMed  Google Scholar 

  27. Tamura A, Wakabayashi K, Onishi Y, Takeda M, Ikegami Y, Sawada S, Tsuji M, Matsuda Y, Ishikawa T (2007) Re-evaluation and functional classification of non-synonymous single nucleotide polymorphisms of the human ATP-binding cassette transporter ABCG2. Cancer Sci 98:231–239

    CAS  Article  PubMed  Google Scholar 

  28. Urquhart BL, Ware JA, Tirona RG, Ho RH, Leake BF, Schwarz UI, Zaher H, Palandra J, Gregor JC, Dresser GK, Kim RB (2008) Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe. Pharmacogenet Genom 18:439–448. https://doi.org/10.1097/FPC.0b013e3282f974dc

    CAS  Article  Google Scholar 

  29. Ueshima S, Hira D, Fujii R, Kimura Y, Tomitsuka C, Yamane T, Tabuchi Y, Ozawa T, Itoh H, Horie M, Terada T, Katsura T (2017) Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation. Pharmacogenet Genom 27:329–336. https://doi.org/10.1097/FPC.0000000000000294

    CAS  Article  Google Scholar 

  30. Ueshima S, Hira D, Kimura Y, Fujii R, Tomitsuka C, Yamane T, Tabuchi Y, Ozawa T, Itoh H, Ohno S, Horie M, Terada T, Katsura T (2018) Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation. Br J Clin Pharmacol 84:1301–1312. https://doi.org/10.1111/bcp.13561

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41. https://doi.org/10.1159/000180580

    CAS  Article  PubMed  Google Scholar 

  32. Gosselin RC, Adcock DM, Bates SM, Douxfils J, Favaloro EJ, Gouin-Thibault I, Guillermo C, Kawai Y, Lindhoff-Last E, Kitchen S (2018) International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 118:437–450. https://doi.org/10.1055/s-0038-1627480

    Article  PubMed  Google Scholar 

  33. Testa S, Tripodi A, Legnani C, Pengo V, Abbate R, Dellanoce C, Carraro P, Salomone L, Paniccia R, Paoletti O, Poli D, Palareti G, Register ST-L (2016) Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: results observed in four anticoagulation clinics. Thromb Res 137:178–183. https://doi.org/10.1016/j.thromres.2015.12.001

    CAS  Article  PubMed  Google Scholar 

  34. Gutmann H, Hruz P, Zimmermann C, Beglinger C, Drewe J (2005) Distribution of breast cancer resistance protein (BCRP/ABCG2) mRNA expression along the human GI tract. Biochem Pharmacol 70:695–699. https://doi.org/10.1016/j.bcp.2005.05.031

    CAS  Article  PubMed  Google Scholar 

  35. Mao Q, Unadkat JD (2015) Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport–an update. AAPS J 17:65–82. https://doi.org/10.1208/s12248-014-9668-6

    CAS  Article  PubMed  Google Scholar 

  36. Sjostedt N, van den Heuvel J, Koenderink JB, Kidron H (2017) Transmembrane domain single-nucleotide polymorphisms impair expression and transport activity of ABC transporter ABCG2. Pharm Res 34:1626–1636. https://doi.org/10.1007/s11095-017-2127-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Fung KL, Pan J, Ohnuma S, Lund PE, Pixley JN, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM (2014) MDR1 synonymous polymorphisms alter transporter specificity and protein stability in a stable epithelial monolayer. Cancer Res 74:598–608. https://doi.org/10.1158/0008-5472.CAN-13-2064

    CAS  Article  PubMed  Google Scholar 

  38. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478. https://doi.org/10.1073/pnas.050585397

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Dimatteo C, D’Andrea G, Vecchione G, Paoletti O, Tiscia GL, Santacroce R, Correale M, Brunetti N, Grandone E, Testa S, Margaglione M (2016) ABCB1 SNP rs4148738 modulation of apixaban interindividual variability. Thromb Res 145:24–26. https://doi.org/10.1016/j.thromres.2016.07.005

    CAS  Article  PubMed  Google Scholar 

  40. McDonald MG, Au NT, Rettie AE (2015) P450-based drug-drug interactions of amiodarone and its metabolites: diversity of inhibitory mechanisms. Drug Metab Dispos 43:1661–1669. https://doi.org/10.1124/dmd.115.065623

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Ohyama K, Nakajima M, Suzuki M, Shimada N, Yamazaki H, Yokoi T (2000) Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: prediction of in vivo drug interactions. Br J Clin Pharmacol 49:244–253

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Kakumoto M, Takara K, Sakaeda T, Tanigawara Y, Kita T, Okumura K (2002) MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs. Biol Pharm Bull 25:1604–1607

    CAS  Article  PubMed  Google Scholar 

  43. Hirsh Raccah B, Rottenstreich A, Zacks N, Muszkat M, Matok I, Perlman A, Kalish Y (2018) Drug interaction as a predictor of direct oral anticoagulant drug levels in atrial fibrillation patients. J Thromb Thrombolysis 46:521–527. https://doi.org/10.1007/s11239-018-1738-7

    CAS  Article  PubMed  Google Scholar 

  44. Caughey GE, Kalisch Ellett LM, Barratt JD, Shakib S (2017) Apixaban, concomitant medicines and spontaneous reports of haemorrhagic events. Ther Adv Drug Saf 8:157–164. https://doi.org/10.1177/2042098616689771

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, See LC, Kuo CF (2017) Association between use of non-vitamin k oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA 318:1250–1259. https://doi.org/10.1001/jama.2017.13883

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Lupercio F, Romero J, Peltzer B, Maraboto C, Briceno D, Villablanca P, Ferrick K, Gross JN, Kim S, Fisher J, Di Biase L, Krumerman A (2018) Efficacy and safety outcomes of direct oral anticoagulants and amiodarone in patients with atrial fibrillation. Am J Med 131(573):e1–e8. https://doi.org/10.1016/j.amjmed.2017.11.047

    CAS  Article  Google Scholar 

  47. Flaker G, Lopes RD, Hylek E, Wojdyla DM, Thomas L, Al-Khatib SM, Sullivan RM, Hohnloser SH, Garcia D, Hanna M, Amerena J, Harjola VP, Dorian P, Avezum A, Keltai M, Wallentin L, Granger CB (2014) Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. J Am Coll Cardiol 64:1541–1550. https://doi.org/10.1016/j.jacc.2014.07.967

    CAS  Article  PubMed  Google Scholar 

  48. Becquemont L, Neuvonen M, Verstuyft C, Jaillon P, Letierce A, Neuvonen PJ, Funck-Brentano C (2007) Amiodarone interacts with simvastatin but not with pravastatin disposition kinetics. Clin Pharmacol Ther 81:679–684. https://doi.org/10.1038/sj.clpt.6100098

    CAS  Article  PubMed  Google Scholar 

  49. Mousa O, Brater DC, Sunblad KJ, Hall SD (2000) The interaction of diltiazem with simvastatin. Clin Pharmacol Ther 67:267–274. https://doi.org/10.1067/mcp.2000.104609

    CAS  Article  PubMed  Google Scholar 

  50. Patel JP, Byrne RA, Patel RK, Arya R (2019) Progress in the monitoring of direct oral anticoagulant therapy. Br J Haematol 184:912–924. https://doi.org/10.1111/bjh.15756

    Article  PubMed  Google Scholar 

  51. Pollak PT, Mitchel LB (2019) Monitoring direct oral anticoagulants: longing for the dayswhen we were in control? Can J Cardiol 35:694–698

    Article  PubMed  Google Scholar 

  52. Testa S, Paoletti O, Legnani C, Dellanoce C, Antonucci E, Cosmi B, Pengo V, Poli D, Morandini R, Testa R, Tripodi A, Palareti G (2018) Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost 16:842–848. https://doi.org/10.1111/jth.14001

    CAS  Article  PubMed  Google Scholar 

  53. Kitchen S, Gray E, Mackie I, Baglin T, Makris M, Committee B (2014) Measurement of non-coumarin anticoagulants and their effects on tests of Haemostasis: guidance from the British Committee for Standards in Haematology. Br J Haematol 166:830–841. https://doi.org/10.1111/bjh.12975

    CAS  Article  PubMed  Google Scholar 

  54. Di Gennaro L, Lancellotti S, De Cristofaro R, De Candia E (2019) Carbamazepine interaction with direct oral anticoagulants: help from the laboratory for the personalized management of oral anticoagulant therapy. J Thromb Thrombolysis. https://doi.org/10.1007/s11239-019-01866-1

    Article  PubMed  Google Scholar 

  55. Dagan G, Perlman A, Hochberg-Klein S, Kalish Y, Muszkat M (2018) Managing direct oral anticoagulants in patients with antiepileptic medication. Can J Cardiol 34(1534):e1–e3. https://doi.org/10.1016/j.cjca.2018.08.001

    Article  Google Scholar 

  56. Pollak PT, Sun GR, Kim RB (2018) Personalized anticoagulation: guided apixaban dose adjustment to compensate for pharmacokinetic abnormalities related to Short-Bowel syndrome. Can J Cardiol 34(342):e17–e19. https://doi.org/10.1016/j.cjca.2017.12.021

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank Racquel Jandoc for help with clinical data entry. This work was supported by the Wolfe Medical Research Chair in Pharmacogenomics, the Ontario Ministry of Research, Innovation and Science (Ontario Research Fund—Research Excellence [RE08-063], Principal Investigator: Kim RB), and the Canadian Institutes of Health Research: Drug Safety and Effectiveness Network [DSEN-PREVENT, FRN-117588], Principal Investigator: Kim RB; Personalized Health Catalyst Grant [PCG-154864], Principal Investigator: Schwarz UI.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ute I. Schwarz.

Ethics declarations

Conflict of interest

Authors have no conflict of interest to disclose.

Ethics Approval

This study involving adult patients has been approved by the Research Ethics Board of Western University, London, Canada (REB15586).

Informed Consent

All subjects provided written informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 232 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gulilat, M., Keller, D., Linton, B. et al. Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care. J Thromb Thrombolysis 49, 294–303 (2020). https://doi.org/10.1007/s11239-019-01962-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-019-01962-2

Keywords

  • Atrial fibrillation
  • Apixaban
  • Pharmacokinetics
  • Breast cancer resistance protein genotype
  • Concomitant amiodarone