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Intestinal Efflux Transporters P-gp and BCRP Are Not Clinically Relevant in Apixaban Disposition

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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 apixaban disposition based on in vitro studies. Recommendations against co-administration of apixaban with inhibitors of these efflux transporters can be found throughout the literature as well as in the apixaban FDA label. However, the clinical relevance of such findings is questionable due to the high permeability and high solubility characteristics of apixaban.

Methods

Using recently published methodologies to discern metabolic- from transporter- mediated drug-drug interactions, a critical evaluation of all published apixaban drug-drug interaction studies was conducted to investigate the purported clinical significance of efflux transporters in apixaban disposition.

Results

Rational examination of these clinical studies using basic pharmacokinetic theory does not support the clinical significance of intestinal efflux transporters in apixaban disposition. Further, there is little evidence that efflux transporters are clinically significant determinants of systemic clearance.

Conclusions

Inhibition or induction of intestinal CYP3A4 can account for exposure changes of apixaban in all clinically significant drug-drug interactions, and lack of intestinal CYP3A4 inhibition can explain all studies with no exposure changes, regardless of the potential for these perpetrators to inhibit intestinal or systemic efflux transporters.

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Abbreviations

AUC :

Area under the concentration-time curve

AUMC :

Area under the moment-time curve

BCRP:

Breast Cancer Resistance Protein

BDDCS:

Biopharmaceutics Drug Disposition Classification System

CL :

Clearance

CL/F :

Apparent clearance

C max :

Maximum concentration in systemic circulation

C max,u :

Maximum unbound concentration in systemic circulation

CYP:

Cytochrome P450

DDI:

Drug-drug interaction

F :

Bioavailability

FDA:

Food and Drug Administration

f u,plasma :

Fraction unbound in plasma

IC 50 :

Half maximal inhibitory concentration

I gut :

Maximum perpetrator concentration in the gut

IV:

Intravenous

k a :

Absorption rate constant

MAT :

Mean absorption time

MRT :

Mean residence time

P-gp:

P-glycoprotein

t max :

Time to maximum concentration

t 1/2,z :

Terminal half-life

V ss :

Volume of distribution at steady-state

Vss/F:

Apparent volume of distribution at steady-state

References

  1. ELIQUIS. (apixaban) [package insert]. Princeton: Bristol-Myers Squibb Company; 2012.

    Google Scholar 

  2. Jacqueroux E, Mercier C, Margelidon-Cozzolino V, Hodin S, Bertoletti L, Delavenne X. In vitro assessment of P-gp and BCRP transporter-mediated drug-drug interactions of riociguat with direct oral anticoagulants. Fundam Clin Pharmacol. 2020;34(1):109–19.

    CAS  PubMed  Google Scholar 

  3. Zhang D, He K, Herbst JJ, Kolb J, Shou W, Wang L, et al. Characterization of efflux transporters involved in distribution and disposition of apixaban. Drug Metab Dispos. 2013;41(4):827–35.

    CAS  PubMed  Google Scholar 

  4. Wu C-Y, 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.

    CAS  PubMed  Google Scholar 

  5. Benet LZ, Bowman CM, Koleske ML, Rinaldi CL, Sodhi JK. Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs. J Pharmacokinet Pharmacodyn. 2019;46(2):155–63.

    CAS  PubMed  Google Scholar 

  6. Sodhi JK, Huang CH, Benet LZ. Volume of distribution is unaffected by metabolic drug-drug interactions. Clin Pharmacokinet. [E-pub ahead of print, July 28, 2020].

  7. Benet LZ, Bowman CM, Sodhi JK. How transporters have changed basic pharmacokinetic understanding. AAPS J. 2019;21(6):103.

    PubMed  Google Scholar 

  8. Grover A, Benet LZ. Effects of drug transporters on volume of distribution. AAPS J. 2009;11(2):250–61.

    CAS  PubMed  Google Scholar 

  9. Benet LZ, Galeazzi RL. Noncompartmental determinations of the steady-state volume of distribution. J Pharm Sci. 1979;68(8):1071–4.

    CAS  PubMed  Google Scholar 

  10. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. In vitro drug interaction studies – cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry. Silver Spring, MD; 2020.

  11. 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.

    PubMed  Google Scholar 

  12. Benet LZ, Bowman CM, Liu S, Sodhi JK. The extended clearance concept following oral and intravenous dosing: theory and critical analyses. Pharm Res. 2018;35(12):242.

    PubMed  Google Scholar 

  13. Cheong J, Halladay JS, Plise E, Sodhi JK, Salphati L. The effects of drug metabolizing enzymes inhibitors on hepatic efflux and uptake transporters. Drug Metab Lett. 2017;11(2):111–8.

    CAS  PubMed  Google Scholar 

  14. Kimoto E, Mathialagan S, Tylaska L, Niosi M, Lin J, Carlo AA, et al. Organic anion transporter 2-mediated hepatic uptake contributes to the clearance of high-permeability-low-molecular-weight acid and zwitterion drugs: evaluation using 25 drugs. J Pharmacol Exp Ther. 2018;367(2):322–34.

    CAS  PubMed  Google Scholar 

  15. Sato T, Mishima E, Mano N, Abe T, Yamaguchi H. Potential drug interactions mediated by renal organic anion transporter OATP4C1. J Pharmacol Exp Ther. 2017;362(2):271–7.

    CAS  PubMed  Google Scholar 

  16. Zamek-Gliszczynski MJ, Taub ME, Chothe PP, Chu X, Giacomini KM, Kim RB, et al. International transporter consortium. Transporters in drug development: 2018 ITC recommendations for transporters of emerging clinical importance. Clin Pharmacol Ther. 2018;104(5):890–9.

    PubMed  Google Scholar 

  17. Alluri RV, Li R, Varma MVS. Transporter-enzyme interplay and the hepatic drug clearance: what have we learned so far? Expert Opin Drug Metab Toxicol. 2020;16(5):387–401.

    CAS  PubMed  Google Scholar 

  18. Varma MV, El-Kattan AF. Transporter-enzyme interplay: deconvoluting effects of hepatic transporters and enzymes on drug disposition using static and dynamic mechanistic models. J Clin Pharmacol. 2016;56:S99–S109.

    CAS  PubMed  Google Scholar 

  19. Sodhi JK, Benet LZ. A simple methodology to differentiate changes in bioavailability from changes in clearance following oral dosing of metabolized drugs. Clin Pharmacol Ther. 2020;108(2):306–15.

    CAS  PubMed  Google Scholar 

  20. 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;22:111.

  21. Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B1 transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81(2):194–204.

    CAS  PubMed  Google Scholar 

  22. Frost C, Song Y, Yu Z, Wang J, Lee LS, Schuster A, et al. The effect of apixaban on the pharmacokinetics of digoxin and atenolol in healthy subjects. Clin Pharmacol. 2017;9:19–28.

    CAS  PubMed  Google Scholar 

  23. Bashir B, Stickle DF, Chervoneva I, Kraft WK. Drug-drug interaction study of apixaban with cyclosporine and tacrolimus in healthy volunteers. Clin Transl Sci. 2018;11(6):590–6.

    CAS  PubMed  Google Scholar 

  24. Frost CE, Byon W, Song Y, Wang J, Schuster AE, Boyd RA, et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol. 2015;79(5):838–46.

    CAS  PubMed  Google Scholar 

  25. Barrett YC, Wang J, Song Y, Pursley J, Wastall P, Wright R, et al. A randomized assessment of the pharmacokinetic, pharmacodynamic and safety interaction between apixaban and enoxaparin in healthy subjects. Thromb Haemost. 2012;107(5):916–24.

    CAS  PubMed  Google Scholar 

  26. Upreti VV, Song Y, Wang J, Byon W, Boyd RA, Pursley JM, et al. Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Clin Pharmacol. 2013;5:59–66.

    CAS  PubMed  Google Scholar 

  27. Mikus G, Foerster KI, Schaumaeker M, Lehmann M-L, Burhenne J, Haefeli WE. Microdosed cocktail of three oral factor Xa inhibitors to evaluate drug-drug interactions with potential perpetrator drugs. Clin Pharmacokinet. 2019;58(9):1155–63.

    CAS  PubMed  Google Scholar 

  28. Frost C, Shenker A, Gandhi MD, Pursley J, Barrett YC, Wang J, et al. Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban. Br J Clin Pharmacol. 2014;78(4):877–85.

    CAS  PubMed  Google Scholar 

  29. Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D, 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.

    CAS  PubMed  Google Scholar 

  30. Wang X, Mondal S, Wang J, Tirucherai G, Zhang D, Boyd RA, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014;14(2):147–54.

    PubMed  Google Scholar 

  31. Kryukov AV, Sychev DA, Andreev DA, Ryzhikova KA, Grishina EA, Ryabova AV, et al. Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke. Pharmgenomics Pers Med. 2018;11:43–9.

    CAS  PubMed  Google Scholar 

  32. Ueshima S, Hira D, Fujii R, Kimura Y, Tomitsuka C, Yamane T, 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.

    CAS  PubMed  Google Scholar 

  33. Lombardo F, Berellini G, Obach RS. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 1352 drug compounds. Drug Metab Dispos. 2018;46(11):1466–77.

    CAS  PubMed  Google Scholar 

  34. Maréchal J-D, Yu J, Brown S, Kapelioukh I, Rankin EM, Wolf CR, et al. In silico and in vitro screening for inhibition of cytochrome P450 CYP3A4 by comedications commonly used by patients with cancer. Drug Metab Dispos. 2006;34(4):534–8.

    PubMed  Google Scholar 

  35. Hulskotte E, Gupta S, Xuan F, van Zutven M, O’Mara E, Feng H-P, et al. Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology. 2012;56(5):1622–30.

    CAS  PubMed  Google Scholar 

  36. Donato MT, Jiménez N, Castell JV, Gómez-Lechón MJ. Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes. Drug Metab Dispos. 2004;32(7):699–706.

    CAS  PubMed  Google Scholar 

  37. 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.

    CAS  PubMed  Google Scholar 

  38. Miyata H, Takada T, Toyoda Y, Matsuo H, Ichida K, Suzuki H. Identification of febuxostat as a new strong ABCG2 inhibitor: potential applications and risks in clinical situations. Front Pharmacol. 2016;7:518.

    PubMed  Google Scholar 

  39. Patel CG, Li L, Girgis S, Kornhauser DM, Frevert EU, Boulton DW. Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole. Clin Pharmacol. 2011;3:13–25.

    CAS  PubMed  Google Scholar 

  40. Burt HJ, Galetin A, Houston JB. IC50-based approaches as an alternative method for assessment of time-dependent inhibition of CYP3A4. Xenobiotica. 2010;40(5):331–43.

    CAS  PubMed  Google Scholar 

  41. Ma B, Preuksaritanont T, Lin JH. Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000;28(2):125–30.

    CAS  PubMed  Google Scholar 

  42. Wang J-S, Wen X, Backman JT, Taavitsainen P, Neuvonen PJ, Kivistö KT. Midazolam alpha-hydroxylation by human liver microsomes in vitro: inhibition by calcium channel blockers, itraconazole, and ketoconazole. Pharmacol Toxicol. 1999;85(4):157–61.

    CAS  PubMed  Google Scholar 

  43. Ellens H, Deng S, Coleman J, Bentz J, Taub ME, Ragueneau-Majlessi I, Chung SP, Herédi-Szabó K, Neuhoff S, Palm J, Balimane P, Zhang L, Jamei M, Hanna I, O’Connor M, Bednarczyk D, Forsgard M, Chu X, Funk C, Guo A, Hillgren KM, Li L, Pak AY, Perloff ES, Rajaraman G, Salphati L, Taur J-S, Weitz D, Wortelboer HM, Xia CQ, Xiao G, Yamagata T, Lee CA. Application of receiver operating characteristic analysis to refine the prediction of potential digoxin drug interactions. Drug Metab Dispos. 2013;41(7):1367–74.

  44. Zhang Y, Gupta A, Wang H, 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.

    CAS  PubMed  Google Scholar 

  45. Isoherranen N, Lutz JD, Chung SP, Hachad H, Levy RH, Ragueneau-Majlessi I. Importance of multi-P450 inhibition in drug-drug interactions: evidence of incidence, inhibition magnitude, and prediction from in vitro data. Chem Res Toxicol. 2012;25(11):2285–300.

    CAS  PubMed  Google Scholar 

  46. Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama MM. The antithrombotic activity and pharmacokinetics of enoxaparine, a low molecular weight heparin in humans given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol. 1988;28(7):609–18.

    CAS  PubMed  Google Scholar 

  47. Lin JH, Chremos AN, Kanovsky SM, Schwartz S, Yeh KC, Kann J. Effects of antacids and food on absorption of famotidine. Br J Clin Pharmacol. 1987;24(4):551–3.

    CAS  PubMed  Google Scholar 

  48. Moody DE, Liu F, Fang WB. In vitro inhibition of methadone and oxycodone cytochrome P450-dependent metabolism: reversible inhibition by H2-receptor agonists and proton-pump inhibitors. J Anal Toxicol. 2013;37(8):476–85.

    CAS  PubMed  Google Scholar 

  49. Brown HS, Galetin A, Hallifax D, Houston JB. Prediction of in vivo drug-drug interactions from in vitro data: factors affecting prototypic drug-drug interactions involving CYP2C9, CYP2D6 and CYP3A4. Clin Pharmacokinet. 2006;45(10):1035–50.

    CAS  PubMed  Google Scholar 

  50. Badri PS, Dutta S, Wang H, Podsadecki TJ, Polepally AR, Khatri A, et al. Drug interactions with the direct-acting antiviral combination of ombitasvir and paritaprevir-ritonavir. Antimicrob Agents Chemother. 2015;60(1):105–14.

  51. 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.

    PubMed  Google Scholar 

  52. Kajbaf M, Longhi R, Montanari D, Vinco F, Rigo M, Fontana S, et al. A comparative study of the CYP450 inhibition potential of marketed drugs using two fluorescence based assay platforms routinely used in the pharmaceutical industry. Drug Metab Lett. 2011;5(1):30–9.

    CAS  PubMed  Google Scholar 

  53. Saito H, Hirano H, Nakagawa H, Fukami T, Oosumi K, Murakami K, et al. A 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.

    CAS  PubMed  Google Scholar 

  54. Polk RE, Brophy DF, Israel DS, Patron R, Sadler BM, Chittick GE, et al. Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males. Antimicrob Agents Chemother. 2001;45(2):502–8.

    CAS  PubMed  Google Scholar 

  55. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin. Clin Pharmacokinet. 2003;42(9):819–50.

    CAS  PubMed  Google Scholar 

  56. Lemmen J, Tozakidis IEP, Galla H-J. Pregnane X receptor upregulates ABC-transporter Abcg2 and Abcb1 at the blood-brain barrier. Brain Res. 2013;1491:1–13.

    CAS  PubMed  Google Scholar 

  57. Goreczyca L, Aleksunes LM. Transcription factor-mediated regulation of the BCRP/ABCG2 efflux transporter: a review across tissues and species. Expert Opin Drug Metab Toxicol. 2020;16(3):239–53.

    Google Scholar 

  58. Bekersky I, Dressler D, Colburn W, Mekki Q. Bioequivalaence of 1 and 5 mg tacrolimus capsules using a replicate study design. J Clin Pharmacol. 1999;39:1032–7.

    CAS  PubMed  Google Scholar 

  59. Amundsen R, Åsberg A, Ohm IK, Christensen H. Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro. Drug Metab Dispos. 2012;40(4):655–61.

    CAS  PubMed  Google Scholar 

  60. Kishimoto W, Ishiguro N, Ludwig-Schwellinger E, Ebner T, Schaefer O. In vitro predictability of drug-drug interaction likelihood of p-glycoprotein-mediated efflux of dabigatran etexilate based on [I]2/IC50 threshold. Drug Metab Dispos. 2014;42(2):257–63.

    CAS  PubMed  Google Scholar 

  61. Patil AG, D’Souza R, Dixit N, Damre A. Validation of quinidine as a probe substrate for the in vitro P-gp inhibition assay in Caco-2 cell monolayer. Eur J Drug Metab Pharmacokinet. 2011;36(3):115–9.

    CAS  PubMed  Google Scholar 

  62. Gupta A, Dai Y, Vethanayagam RR, Hebert MF, Thummel KE, Unadkat JD, et al. Cyclosporine A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan. Cancer Chemother Pharmacol. 2006;58(3):374–83.

    CAS  PubMed  Google Scholar 

  63. Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, 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.

    CAS  PubMed  Google Scholar 

  64. Yavorski RT, Hallgren SE, Blue PW. Effects of verapamil and diltiazem on gastric emptying in normal subjects. Dig Dis Sci. 1991;36(9):1274–6.

    CAS  PubMed  Google Scholar 

  65. Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos. 2009;37(1):74–81.

    CAS  PubMed  Google Scholar 

  66. Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet. 2019;58(10):1265–79.

    PubMed  Google Scholar 

  67. Prom R, Spinler SA. The role of apixaban for venous and arterial thromboembolic disease. Ann Pharmacother. 2011;45(10):1262–83.

    CAS  PubMed  Google Scholar 

  68. Budovich A, Zargarova O, Nogid A. Role of apixaban (eliquis) in the treatment and prevention of thromboembolic disease. Pharm Ther. 2013;38(4):206–31.

    Google Scholar 

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

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine, University of California San Francisco, 513 Parnassus Ave Rm HSE 1164, UCSF Box 0912, San Francisco, California, 94143, USA

    Jasleen K. Sodhi, Shuaibing Liu & Leslie Z. Benet

  2. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Shuaibing Liu

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  1. Jasleen K. Sodhi
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  2. Shuaibing Liu
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  3. Leslie Z. Benet
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Correspondence to Leslie Z. Benet.

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Sodhi, J.K., Liu, S. & Benet, L.Z. Intestinal Efflux Transporters P-gp and BCRP Are Not Clinically Relevant in Apixaban Disposition. Pharm Res 37, 208 (2020). https://doi.org/10.1007/s11095-020-02927-4

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