Pharmacokinetics and Pharmacogenetics of Apixaban

Apixaban is oral anticoagulant, it is widely used in prevention of stroke in non-valvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Its main mechanism of action is through reversible inhibition of factor Xa. It specifically binds and inhibits both free and bound factor Xa which ultimately results in reduction in the levels of thrombin formation. Apixaban is mainly metabolized by CYP3A4 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2J2 isoenzymes. Some of the major metabolic pathways of apixaban include o-demethylation, hydroxylation, and sulfation, with o-demethylapixabansulphate being the major metabolite. The aim of this review is analysis of associated researches of single nucleotide variants (SNV) of CYP3A5 and SULT1A1 genes and search for new candidate genes reflecting effectiveness and safety of apixaban. The search for full-text publications in Russian and English languages containing key words “apixaban”, “pharmacokinetics”, “effectiveness”, “safety” was carried out amongst literature of the past twenty years with the use of eLibrary, PubMed, Web of Science, OMIM data bases. Pharmacokinetics and pharmacogenetics of apixaban are considered in this review. The hypothesis about CYP и SULT1A enzymes influence on apixaban metabolism was examined. To date, numerous SNVs of the CYP3A5 and SULT1A1 genes have been identified, but their potential influence on pharmacokinetics apixaban in clinical practice needs to be further studies. The role of SNVs of other genes encoding beta-oxidation enzymes of apixaban (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2) and transporter proteins (ABCB1, ABCG2) in its efficacy and safety are not well understood, and ABCB1 and ABCG2 genes may be potential candidate genes for studies of the drug safety.

1. Bristol-Myers Squibb. Coumadin (warfarin sodium) prescribing information [cited by Sep 19, 2020]. Available from: https://packageinserts.bms.com/pi/pi_coumadin.pdf.

2. Lip G.Y.H., Banerjee A., Boriani G., et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest. 2018;154(5):1121-201. DOI:10.1016/j.chest.2018.07.040.

3. Rubanenko O.A. Anticoagulant therapy in comorbidal patients with different forms of fibrillation of auricles (retrospective hospital analysis). Siberian Medical Review. 2017;2:71-6 (In Russ.)

4. European Medicines Agency. EU summary of product characteristics: Eliquis (apixaban tablets) [cited by Sep 19, 2020]. Available from: https://www.ema.europa.eu/en/documents/product-information/eliquis-epar-product-information_en.pdf.

5. Bristol-Myers Squibb Company PI. Eliquis (apixaban) prescribing information [cited by Sep 19, 2020]. Available from: https://packageinserts.bms.com/pi/pi_eliquis.pdf.

6. Sychev D.A., Sinitsina I.I., Zakharova G.Yu., et al. Practical aspects of apixaban use in clinical practice: view point of clinical pharmacologist. Rational Pharmacotherapy in Cardiology. 2015;11(2):209-16 (In Russ.) DOI:10.20996/1819-6446-2015-11-2-209-216.

7. Bel'diev S.N. Practical aspects of apixaban use in clinical practice: continuing the theme. Rational Pharmacotherapy in Cardiology. 2015;11(5):543-7 (In Russ.) DOI:10.20996/1819-6446-2015-11-5-543-547.

8. Granger C.B., Alexander J.H., McMurray J.J., et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92. DOI:10.1056/NEJMoa1107039.

9. Karpov Yu.A. Apixaban: new opportunities for prevention of complications in patients with atrial fibrillation. Atmosphere. Cardiology News. 2013;4:2-8 (In Russ.)

10. Connolly S.J., Eikelboom J., Joyner C., et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-17. DOI:10.1056/NEJMoa1007432.

11. Kryukov A.V., Sychev D.A., Andreev D.A., et al. The pharmacokinetics of apixaban in patients with cardioembolic stroke in acute phase. Rational Pharmacotherapy in Cardiology. 2016;12(3):253-9 (In Russ.) DOI:10.20996/1819-6446-2016-12-3-253-259.

12. Lassen M.R., Raskob G.E., Gallus A., et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375(9717):807- 15. DOI:10.1016/S0140-6736(09)62125-5.

13. Vorob'eva N.M., Panchenko E.P. Apixaban: new opportunities in the treatment of venous thromboembolic complications. Atmosphere. Cardiology News. 2015;2:10-17 (In Russ.)

14. Agnelli G., Buller H.R., Cohen A., et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808. DOI:10.1056/NEJMoa1302507.

15. Agnelli G., Buller H.R., Cohen A., et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699-708. DOI:10.1056/NEJMoa1207541.

16. Drugs.com. FDA Approves Eliquis to Reduce the Risk of Stroke, Blood Clots in Patients with NonValvular Atrial Fibrillation [cited by Sep 19, 2020]. Available from: https://www.drugs.com/newdrugs/fda-approves-eliquis-reduce-risk-stroke-blood-clots-patients-non-valvular-atrial-fibrillation-3618.html.

17. Parfenov V., Verbitskaya S. Secondary prevention of stroke in atrial fibrillation, use of apixaban: ARISTOTLE, AVERROES studies. Neurology, Neuropsychiatry, Psychosomatics. 2014;6(2S):7-14 (In Russ.) DOI:10.14412/2074-2711-2014-2S7-14.

18. Drugs.com. FDA Approves Eliquis to Reduce Risk of Blood Clots Following Hip Or Knee Replacement Surgery [cited by Sep 19, 2020]. Available from: https://www.drugs.com/newdrugs/fda-approveseliquis-reduce-risk-blood-clots-following-hip-knee-replacement-surgery-4019.html.

19. Drugs.com. FDA Approves Eliquis (apixaban) for the Treatment of Deep Vein Thrombosis and Pulmonary Embolism [cited by Sep 19, 2020]. Available from: https://www.drugs.com/newdrugs/fdaapproves-eliquis-apixaban-deep-vein-thrombosis-pulmonary-embolism-4073.html.

20. Khalid S., Daw H. The Role of Apixaban in the Treatment of Heparin-Induced Thrombocytopenia. Cureus. 2017;9(7):e1428. DOI:10.7759/cureus.1428.

21. Melnichuk E.Yu. Prospective directions of laboratory monitoring of the effectiveness and safety of apixaban and rivaroxaban. Bulletin of the Northern State Medical University. 2018; 2 (41): 70-1 (In Russ.)

22. Skripka A.I., Kogay V.V., Listratov A.I., et al. Personalized approach for direct oral anticoagulant prescription: from theory to practice. Ter Arkhiv. 2019;91(7):111-20 (In Russ.) DOI:10.26442/00403660.2019.07.000045.

23. Luettgen J.M., Knabb R.M., He K., et al. Apixaban inhibition of factor Xa: Microscopic rate constants and inhibition mechanism in purified protein systems and in human plasma. J Enzyme Inhib Med Chem. 2011;26(4):514-26. DOI:10.3109/14756366.2010.535793.

24. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost. 2007;5Suppl 1:60- 4. DOI:10.1111/j.1538-7836.2007.02473.x.

25. Malchenko A.V. Clinical pharmacology of apixaban. International Journal of Applied and Basic Research. 2014;1(1):88-9 (In Russ.)

26. Jiang X., Crain E.J., Luettgen J.M., et al. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xaactivity in vitro. Thromb Haemost. 2009;101(4):780-2. DOI:10.1160/th08-07-0486.

27. Frost C., Wang J., Nepal S., et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J ClinPharmacol. 2013;75(2):476-87. DOI:10.1111/j.1365-2125.2012.04369.x.

28. Frost C., Nepal S,. Wang J., et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013;76(5):776- 86. DOI:10.1111/bcp.12106.

29. Byon W., Nepal S., Schuster A.E., et al. Regional Gastrointestinal Absorption of Apixaban in Healthy Subjects. J Clin Pharmacol. 2018;58(7):965-71. DOI:10.1002/jcph.1097.

30. 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):119-27. DOI:10.1007/s40256-015-0157-9.

31. Raghavan N., Frost C.E., 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.

32. 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 MetabDispos. 2010;38(3):448-58. DOI:10.1124/dmd.109.029694.

33. Zhang D., He K., Herbst J.J., et al. Characterization of efflux transporters involved in distribution and disposition of apixaban. Drug Metab Dispos. 2013;41(4):827-35. DOI:10.1124/dmd.112.050260.

34. 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. ClinTher. 2016;38(7):1674-85.e1. DOI:10.1016/j.clinthera.2016.05.004.

35. 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):1703-12. DOI:10.1016/j.clinthera.2015.05.497.

36. He K., Luettgen J.M., 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- 39. DOI:10.1007/s13318-011-0037-x.

37. Wang X., Tirucherai G., Marbury T.C., et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-36. DOI:10.1002/jcph.628.

38. Wong P.C., Pinto D.J., Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis. 2011;31(4):478-92. DOI:10.1007/s11239-011-0551-3

39. Wang L., He K., Maxwell B., et al. Tissue distribution and elimination of [14C] apixaban in rats. Drug Metab Dispos. 2011;39(2):256-64. DOI:10.1124/dmd.110.036442.

40. Frost C., Shenker A., Jhee S., et al. Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects. Clin Pharmacol. 2018;10:153-163. DOI:10.2147/CPAA.S169505.

41. Cui Y., Song Y., Wang J., et al. Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects. Clin Pharmacol. 2013;5:177-84. DOI:10.2147/CPAA.S51981.

42. 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):147-54. DOI:10.1007/s40256-013-0055-y.

43. Frost C.E., 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):651-62. DOI:10.1007/s40262-014-0228-0.

44. Upreti V.V., Wang J., Barrett Y.C., 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(6):908-16. DOI:10.1111/bcp.12114.

45. Leil T.A., Frost C., Wang X., et al. Model-based exposure-response analysis of apixaban to quantify bleeding risk in special populations of subjects undergoing orthopedic surgery. CPT Pharmacometrics Syst Pharmacol. 2014;3(9):e136. DOI:10.1038/psp.2014.34.

46. Cirincione B., Kowalski K., Nielsen J., et al. Population Pharmacokinetics of Apixaban in Subjects WithNonvalvular Atrial Fibrillation. CPT Pharmacometrics Syst Pharmacol. 2018;7(11):728-738. DOI:10.1002/psp4.12347.

47. Sandhu R.K., Ezekowitz J., Andersson U., et al. The 'obesity paradox' in atrial fibrillation: observations from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Eur Heart J. 2016;37(38):2869-78. DOI:10.1093/eurheartj/ehw124.

48. Byon W., Sweeney K., Frost C., Boyd R.A. Population Pharmacokinetics, Pharmacodynamics, and Exploratory Exposure-Response Analyses of Apixaban in Subjects Treated for Venous Thromboembolism. CPT Pharmacometrics Syst Pharmacol. 2017;6(5):340-9. DOI:10.1002/psp4.12184.

49. Goto S., Zhu J., Liu L., et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Am Heart J. 2014;168(3):303-9. DOI:10.1016/j.ahj.2014.06.005.

50. 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):637-45. DOI:10.1002/jcph.633.

51. Tirona R.G., Kassam Z., Strapp R., et al. Apixaban and Rosuvastatin Pharmacokinetics in Nonalcoholic Fatty Liver Disease. Drug Metab Dispos. 2018;46(5):485-92. DOI:10.1124/dmd.117.079624.

52. Ueshima S., Hira D., Fujii R., Kimura Y., et al. Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation. Pharmacogenet Genomics. 2017;27(9):329-36. DOI:10.1097/FPC.0000000000000294.

53. SNPedia. CYP3A5 [cited by Sep 19, 2020]. Available from: https://www.snpedia.com/index.php/CYP3A5.

54. Kang R.H., Jung S.M., Kim K.A., et al. Effects of CYP2D6 and CYP3A5 genotypes on the plasma concentrations of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients. J Clin Psychopharmacol. 2009;29(3):272-7. DOI:10.1097/JCP.0b013e3181a289e0.

55. Umamaheswaran G., Kumar D.K., Adithan C. Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective. Indian J Med Res. 2014;139(1):27-65

56. Canonico M., Bouaziz E., Carcaillon L., et al. Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women. J Clin Endocrinol Metab. 2008;93(8):3082-7. DOI:10.1210/jc.2008-0450.

57. SNPedia. CYP1A2 [cited by Sep 19, 2020]. Available from: https://www.snpedia.com/index.php/CYP1A2.

58. Kanuri S.H., Kreutz R.P. Pharmacogenomics of novel direct oral anticoagulants: newly identified genes and genetic variants. J Pers Med. 2019; 9(1):7. DOI:10.3390/jpm9010007.

59. Sweezy T., Mousa S.A. Genotype-guided use of oral antithrombotic therapy: A pharmacoeconomic perspective. Pers. Med. 2014;11:223-35. DOI:10.2217/pme.13.106.

60. Carlini E.J., Raftogianis R.B., Wood T.C., et al. Sulfation pharmacogenetics: SULT1A1 and SULT1A2 allele frequencies in Caucasian, Chinese and African-American subjects. Pharmacogenetics. 2001;11:57-68. DOI:10.1097/00008571-200102000-00007.

61. Wang L., Raghavan N., He K., et al. Sulfation of o-DemethylApixaban: Enzyme Identification and Species Comparison. Drug Metab Dispos. 2009;37:802-8. DOI:10.1124/dmd.108.025593.

62. Nagar S., Walther S., Blanchard R.L. Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation. Mol Pharmacol. 2006;69:2084-92. DOI:10.1124/mol.105.019240.

63. Raftogianis R.B., Wood T.C., Otterness D.M., et al. Phenol SulfotransferasePharmacogenetics in Humans: Association of Common SULT1A1 Alleles with TS PST Phenotype. Biochem Biophys Res Commun. 1997;239:298-304. DOI:10.1006/bbrc.1997.7466.

64. Dimatteo C., D’Andrea G., Vecchione G., et al. ABCB1 SNP rs4148738 modulation of apixaban interindividual variability. Thromb Res. 2016;145:24-6. DOI:10.1016/j.thromres.2016.07.005.

65. Xie Q., Xiang Q., Mu G., et al. Effect of ABCB1 Genotypes on the Pharmacokinetics and Clinical Outcomes of New Oral Anticoagulants: A Systematic Review and Meta-analysis. Curr Pharm Des. 2018;24(30):3558-65. DOI:10.2174/1381612824666181018153641.

66. Kryukov A.V., Sychev D.A., Andreev D.A., et al. Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke. Pharm Pers Med. 2018;11:43-9. DOI:10.2147/PGPM.S157111.

67. Cusatis G., Sparreboom A. Pharmacogenomic importance of ABCG2. Pharmacogenomics. 2008; 9(8):1005-9. DOI:10.2217/14622416.9.8.1005.

68. Cusatis G., Gregorc V., Li J., et al. Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. Journal of the National Cancer Institute. 2006;98(23):1739-42. DOI:10.1093/jnci/djj469.

69. Woodward O.M., Tukaye D.N., Cui J., et al. Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules. Proceedings of the National Academy of Sciences U S A. 2013;110(13):5223-8. DOI:10.1073/pnas.1214530110.

70. O’Connor C.T., KiernanT.J., Yan B.P. The genetic basis of antiplatelet and anticoagulant therapy: A pharmacogenetic review of newer antiplatelets (clopidogrel, prasugrel and ticagrelor) and anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban). Expert Opin Drug Metab Toxicol. 2017 Jul;13(7):725-39. DOI:10.1080/17425255.2017.1338274.

71. Ueshima S., Hira D., Kimura Y., et al. Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation. Br J Clin Pharmacol. 2018;84(6):1301-12. DOI:10.1111/bcp.13561.