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Investigating Intestinal Transporter Involvement in Rivaroxaban Disposition through Examination of Changes in Absorption

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Abstract

Purpose

The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in rivaroxaban disposition based on in vitro studies, similar to what had previously been proposed for apixaban. We recently showed that these efflux transporters were not clinically relevant for apixaban disposition and examine here their relevance for this second Factor Xa inhibitor.

Methods

Using recently published methodologies to discern metabolic- from transporter- mediated drug interactions, a critical evaluation was undertaken of 9 rivaroxaban studies reporting 12 DDIs, one study of food effects and one study of hepatic function.

Results

Rationale examination of these clinical studies using basic pharmacokinetic theory finds little support for the clinical significance of intestinal efflux transporters in rivaroxaban disposition. Drug-drug interactions are most likely adequately predicted based on the level of CYP 3A metabolism.

Conclusion

These analyses indicate that inhibition of efflux transporters appears to have negligible, clinically insignificant effects on the rivaroxaban absorption process, which is consistent with the concern that predictions based on in vitro measures may not translate to a clinically relevant interaction in vivo. We emphasize the need to evaluate gastric emptying, dissolution and other processes related to absorption when using MAT changes to indicate efflux transporter inhibition.

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Abbreviations

AUC:

Area under the curve

AUMC:

Area under the moment time curve

BCRP:

Breast cancer resistance protein

CL/F:

Apparent clearance

Cmax :

Maximum concentration

CYP:

Cytochrome P450

DDIs:

Drug-drug interactions

Igut :

Maximum perpetrator concentration in gut

MAT:

Mean absorption time

MRT:

Mean residence time

P-gp:

P-glycoprotein

SJW:

St. John’s Wort

tmax :

Time of maximum concentration

t1/2 :

Terminal half-life

References

  1. Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation? Ann Pharmacother. 2013;47(11):1478–87.

    Article  CAS  PubMed  Google Scholar 

  2. Mega JL, Simon T. Pharmacology of antithrombotic drugs: an assessment of oral antiplatelet and anticoagulant treatments. Lancet. 2015;386(9990):281–91.

    Article  CAS  PubMed  Google Scholar 

  3. Plitt A, Ruff CT, Giugliano RP. Non-vitamin K antagonist oral anticoagulants in atrial fibrillation. Hematol Oncol Clin North Am. 2016;30(5):1019–34.

    Article  PubMed  Google Scholar 

  4. Nutescu EA, Burnett A, Fanikos J, Spinler S, Wittkowsky A. Pharmacology of anticoagulants used in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):15–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Buller HR, Lensing AW, Prins MH, Agnelli G, Cohen A, Gallus AS, et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT dose-ranging study. Clin Trials Observ. 2008;112(6):2242–7.

    CAS  Google Scholar 

  6. Goodman SG, Wojdyla DM, Piccini JP, White HD, Paolini JF, Nessel CC, et al. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2014;63(9):891–900.

    Article  PubMed  Google Scholar 

  7. Sodhi JK, Liu S, Benet LZ. Intestinal efflux transporters P-gp and BCRP are not clinically relevant in apixaban disposition. Pharm Res. 2020;37(10):208.

    Article  CAS  PubMed  Google Scholar 

  8. Wu CY, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/ elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22(1):11–23.

    Article  CAS  PubMed  Google Scholar 

  9. Shugarts S, Benet LZ. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res. 2009;26(9):2039–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet. 2014;53(1):1–16.

    Article  CAS  PubMed  Google Scholar 

  11. Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos. 2009;37(5):1056–64.

    Article  CAS  PubMed  Google Scholar 

  12. Rivaroxaban package insert. Full prescribing information.2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202439s031,022406s035lbl.pdf. Accessed Dec 2020.

  13. Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol. 2013;29(7):S24–33.

    Article  PubMed  Google Scholar 

  14. Schinkel AH, Wagenaar E, Mol CA, Deemter LV. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97(11):2517–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther. 2011;338(1):372–80.

    Article  CAS  PubMed  Google Scholar 

  16. 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):455–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sodhi JK, Benet LZ. The necessity of using changes in absorption time to implicate intestinal transporter involvement in oral drug-drug interactions. AAPS J. 2020;22(5):111.

    Article  CAS  PubMed  Google Scholar 

  18. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban-an oral, direct factor Xa inhibitor-are not affected by aspirin. J Clin Pharmacol. 2006;46(9):981–90.

    Article  CAS  PubMed  Google Scholar 

  19. Cook JA, Feng B, Fenner KS, Kempshall S, Liu R, Rotter C, et al. Refining the in vitro and in vivo critical parameters for P-glycoprotein, [I]/IC50 and [I2]/IC50, that allow for the exclusion of drug candidates from clinical digoxin interaction studies. Mol Pharm. 2010;7(2):398–411.

    Article  CAS  PubMed  Google Scholar 

  20. Eberl S, Renner B, Neubert A, Reisig M, Bachmakov I, König J, et al. Role of P-glycoprotein inhibition for drug interactions: evidence from in vitro and pharmaco epidemiological studies. Clin Pharmacokinet. 2007;46(12):1039–49.

    Article  CAS  PubMed  Google Scholar 

  21. Kellick KA, Bottorff M, Toth PP. The National Lipid Association's safety task force. A clinician's guide to statin drug-drug interactions. J Clin Lipidol. 2014;8:S30–46.

    Article  PubMed  Google Scholar 

  22. Brings A, Lehmann ML, Foerster KI, Burhenne J, Weiss J, Haefeli WE, et al. Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers. Br J Clin Pharmacol. 2019;85(7):1528–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sugimoto H, Matsumoto S, Tachibana M, Niwa S, Hirabayashi H, Amano N, et al. Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage. J Pharm Sci. 2011;100(9):4013–23.

    Article  CAS  PubMed  Google Scholar 

  24. Rautio J, Humphreys JE, Webster LO, Balakrishnan A, Keogh JP, Kunta JR, et al. In vitro P-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: a recommendation for probe substrates. Drug Metab Dispos. 2006;34(5):786–92.

    Article  CAS  PubMed  Google Scholar 

  25. Ozvegy C, Litman T, Szakács G, Nagy Z, Bates S, Váradi A, et al. Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells. Biochem Biophys Res Commun. 2001;285(1):111–7.

    Article  CAS  PubMed  Google Scholar 

  26. Xia CQ, Liu N, Miwa GT, Gan LS. Interactions of cyclosporin A with breast cancer resistance protein. Drug Metab Dispos. 2007;35(4):576–82.

    Article  CAS  PubMed  Google Scholar 

  27. Ekins S, Kim RB, Leake BF, Dantzig AH, Schuetz EG, Lan LB, et al. Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein. Mol Pharmacol. 2002;61(5):964–73.

    Article  CAS  PubMed  Google Scholar 

  28. Eriksson UG, Dorani H, Karlsson J, Fritsch H, Hoffmann KJ, Olsson L, et al. Influence of erythromycin on the pharmacokinetics of ximelagatran may involve inhibition of P-glycoprotein-mediated excretion. Drug Metab Dispos. 2006;34(5):775–82.

    Article  CAS  PubMed  Google Scholar 

  29. Franke RM, Lancaster CS, Peer CJ, Gibson AA, Kosloske AM, Orwick SJ, et al. Effect of ABCC2 (MRP2) transport function on erythromycin metabolism. Clin Pharmacol Ther. 2011;89(5):693–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW. Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother. 2002;46(1):160–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lempers VJC, van den Heuvel JJMW, Russel FGM, Aarnoutse RE, Burger DM, Brüggemann RJ, et al. Inhibitory potential of antifungal drugs on ATP-binding cassette transporters P-gp, MRP1-5, BCRP and BSEP. Antimicrob Agents Chemother. 2016;60(6):3372–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Keogh JP, Kunta JR. Development, validation and utility of an in vitro technique for assessment of potential clinical drug-drug interactions involving P-glycoprotein. Eur J Pharm Sci. 2006;27(5):543–54.

    Article  CAS  PubMed  Google Scholar 

  33. Wang E, Casciano CN, Clement RP, Johnson WW. The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein. Cancer Res. 2001;61(20):7525–9.

    CAS  PubMed  Google Scholar 

  34. Vermeer LMM, Isringhausen CD, Ogilvie BW, Buckley DB. Evaluation of ketoconazole and its alternative clinical CYP3A4/5 inhibitors as inhibitors of drug transporters: the in vitro effects of ketoconazole, ritonavir, clarithromycin, and itraconazole on 13 clinically-relevant drug transporters. Drug Metab Dispos. 2016;44(3):453–9.

    Article  PubMed  Google Scholar 

  35. Gupta A, Unadkat JD, Mao QC. Interactions of azole antifungal agents with the human breast cancer resistance protein (BCRP). J Pharm Sci. 2007;96(12):3226–35.

    Article  CAS  PubMed  Google Scholar 

  36. Huppertz A, Werntz L, Meid AD, Foerster KI, Burhenne J, Czock D, et al. Rivaroxaban and macitentan can be co administered without dose adjustment but the combination of rivaroxaban and St John’s Wort should be avoided. Br J Clin Pharmacol. 2018;84(12):2903–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Weiss J, Theile D, Ruppell MA, Speck T, Spalwisz A, Haefeli WE. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol. 2013;701(1–3):168–75.

    Article  CAS  PubMed  Google Scholar 

  38. Lepist EI, Gillies H, Smith W, Hao J, Hubert C, St Claire RL, et al. Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes. PLoS One. 2014;9(1):e87548.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY 59-7939) - an oral, direct factor Xa inhibitor - has no clinically relevant interaction with naproxen. Br J Clin Pharmacol. 2006;63(4):469–76.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Saito H, Hirano H, Nakagawa H, Fukami T, Oosumi K, Murakami KA. New strategy of high-speed screening and quantitative structure-activity relationship analysis to evaluate human ATP-binding cassette transporter ABCG2-drug interactions. J Pharmacol Exp Ther. 2006;317(3):1114–24.

    Article  CAS  PubMed  Google Scholar 

  41. Moore KT, Plotnikov AN, Thyssen A, Vaccaro N, Ariyawansa J, Burton PB. Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban. J Cardiovasc Pharmacol. 2011;58(6):581–8.

    Article  CAS  PubMed  Google Scholar 

  42. Neuhoff S, Langguth P, Dressler C, Andersson TB, Regårdh CG, Spahn-Langguth H. Affinities at the verapamil binding site of MDR1-encoded P-glycoprotein: drugs and analogs, stereoisomers and metabolites. Int J Clin Pharmacol Ther. 2000;38(4):168–79.

    Article  CAS  PubMed  Google Scholar 

  43. Breedveld P, Zelcer N, Pluim D, Sönmezer O, Tibben MM, Beijnen JH, et al. Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004;64(16):5804–11.

    Article  CAS  PubMed  Google Scholar 

  44. Greenblatt DJ, Patel M, Harmatz JS, Nicholson WT, Rubino CM, Chow CR. Impaired rivaroxaban clearance in mild renal insufficiency with verapamil co-administration: potential implications for bleeding risk and dose selection. J Clin Pharmacol. 2018;58(4):533–40.

    Article  CAS  PubMed  Google Scholar 

  45. Römermann K, Wanek T, Bankstahl M, Bankstahl JP, Fedrowitz M, Müller M. (R)-[(11)C] verapamil is selectively transported by murine and human P-glycoprotein at the blood-brain barrier, and not by MRP1 and BCRP. Nucl Med Biol. 2013;40(7):873–8.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Zhang Y, Gupta A, Wang HG, Zhou L, Vethanayagam RR, Unadkat JD, et al. BCRP transports dipyridamole and is inhibited by calcium channel blockers. Pharm Res. 2005;22(12):2023–34.

    Article  CAS  PubMed  Google Scholar 

  47. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006;46(5):549–58.

    Article  CAS  PubMed  Google Scholar 

  48. Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). In vitro drug interaction studies – cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry. 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. Accessed Dec 2020.

  50. Tornio A, Filppula AM, Niemi M, Backman JT. Clinical studies on drug-drug interactions involving metabolism and transport: methodology, pitfalls, and interpretation. Clin Pharmacol Ther. 2019;105(6):1345–61.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Han YR, Lee PI, Pang KS. Finding Tmax and Cmax in multi compartmental models. Drug Metab Dispos. 2018;46(11):1796–804.

    Article  CAS  PubMed  Google Scholar 

  52. Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: A review of fundamentals. J Clin Pharmacol. 2002;42(6):620–43.

    Article  CAS  PubMed  Google Scholar 

  53. Kechagias S, Jonsson KA, Norlander B, Carlsson B, Jones AW. Low-dose aspirin decreases blood alcohol concentrations by delaying gastric emptying. Eur J Clin Pharmacol. 1997;53:241–65.

    Article  CAS  PubMed  Google Scholar 

  54. Leivonen M, Sipponen P, Kivilaakso E. Gastric changes in coronary operated patients with low-dose aspirin. Scand J Gastroenterol. 1992;27(11):912–6.

    Article  CAS  PubMed  Google Scholar 

  55. Prichard PJ, Kitchingman GK, Walt RP, Daneshmend TK, Hawkey CJ. Human gastric mucosal bleeding induced by low-dose aspirin, but not warfarin. BMJ. 1989;298(6672):493–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Soldner A, Christians U, Susanto M, Wacher VJ, Silverman JA, Benet LZ. Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm Res. 1999;16(4):478–85.

    Article  CAS  PubMed  Google Scholar 

  57. Fahmi OA, Maurer TS, Kish M, Cardenas E, Boldt S, Nettleton D. A combined model for predicting CYP3A4 clinical net drug-drug interaction based on CYP3A4 inhibition, inactivation, and induction determined in vitro. Drug Metab Dispos. 2008;36(8):1698–708.

    Article  CAS  PubMed  Google Scholar 

  58. Manda VK, Avula B, Dale OR, Ali Z, Khan IA, Walker LA, et al. PXR mediated induction of CYP3A4, CYP1A2, and P-gp by Mitragyna speciose and its alkaloids. Phytother Res. 2017;31(12):1935–45.

    Article  CAS  PubMed  Google Scholar 

  59. Brage R, Cortijo J, Esplugues J, Esplugues JV, MartiBonmati E, Rodriguez C. Effects of calcium channel blockers on gastric emptying and acid secretion of the rat in vivo. Br J Pharmacol. 1986;89(4):627–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Krevsky B, Maurer AH, Niewiarowski T, Cohen S. Effect of verapamil on human intestinal transit. Dig Dis Sci. 1992;37(6):919–24.

    Article  CAS  PubMed  Google Scholar 

  61. Dhillon S. Macitentan: A review of its use in patients with pulmonary arterial hypertension. Drugs. 2014;74(13):1495–507.

    Article  CAS  PubMed  Google Scholar 

  62. Perlo MD, Moltke LV, Störmer E, Shader RI, Greenblatt DJ. Saint John's Wort: an in vitro analysis of P-glycoprotein induction due to extended exposure. Br J Clin Pharmacol. 2001;134(8):1601–8.

    Article  Google Scholar 

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ACKNOWLEDGEMENTS AND DISCLOSURES

This work was supported in part by a Mary Ann Koda-Kimble Seed Award for Innovation. Ms. Kou’s stay in the UCSF Benet Laboratory was supported by the Educational Foundation Program of Lanzhou University. Dr. Sodhi was supported in part by an American Foundation for Pharmaceutical Education Predoctoral Fellowship, NIGMS grant R25 GM56847 and a Louis Zeh Fellowship. Dr. Benet is a member of the UCSF Liver Center supported by NIH grant P30 DK026743. All authors contributed to the writing and analysis of this manuscript. The authors declare no conflict of interest.

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Kou, W., Sodhi, J.K., Wu, X. et al. Investigating Intestinal Transporter Involvement in Rivaroxaban Disposition through Examination of Changes in Absorption. Pharm Res 38, 795–801 (2021). https://doi.org/10.1007/s11095-021-03039-3

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