Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

British Journal of Clinical Pharmacology

Volumn 79, Issue 5, 2015, Pages 838-846

  Frost, Charles E ^a   Byon, Wonkyung ^b   Song, Yan ^a   Wang, Jessie ^a   Schuster, Alan E ^a   Boyd, Rebecca A ^b   Zhang, Donglu ^a   Yu, Zhigang ^a,d   Dias, Clapton ^a   Shenker, Andrew ^a,c   Lacreta, Frank ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b PFIZER INC   (United States)

^c GLAXOSMITHKLINE   (United States)

^d GENENTECH INC   (United States)

Author keywords

anticoagulants; apixaban; CYP3A4 inhibitors; drug drug interactions; P glycoprotein inhibitors

Indexed keywords

APIXABAN; CYTOCHROME P450 3A4; DILTIAZEM; KETOCONAZOLE; MULTIDRUG RESISTANCE PROTEIN; BLOOD CLOTTING FACTOR 10A INHIBITOR; CYP3A4 PROTEIN, HUMAN; CYTOCHROME P450 3A; CYTOCHROME P450 3A INHIBITOR; PYRAZOLE DERIVATIVE; PYRIDONE DERIVATIVE;

ADULT; AREA UNDER THE CURVE; ARTICLE; BLEEDING; CLINICAL TRIAL (TOPIC); CONJUNCTIVAL HEMORRHAGE; CONTUSION; DIZZINESS; DRUG BLOOD LEVEL; DRUG EFFECT; DRUG ELIMINATION; DRUG EXCRETION; DRUG EXPOSURE; DRUG HALF LIFE; DRUG METABOLISM; DRUG SAFETY; EPISTAXIS; FEMALE; HEADACHE; HUMAN; HUMAN EXPERIMENT; MALE; NORMAL HUMAN; PAPULAR RASH; PETECHIA; PRIORITY JOURNAL; RASH; SINGLE DRUG DOSE; ADOLESCENT; BLOOD; CLINICAL TRIAL; CROSSOVER PROCEDURE; DOSE RESPONSE; DRUG INTERACTION; METABOLISM; MIDDLE AGED; YOUNG ADULT;

ADOLESCENT; ADULT; CROSS-OVER STUDIES; CYTOCHROME P-450 CYP3A; CYTOCHROME P-450 CYP3A INHIBITORS; DILTIAZEM; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG INTERACTIONS; FACTOR XA INHIBITORS; FEMALE; HEALTHY VOLUNTEERS; HUMANS; KETOCONAZOLE; MALE; MIDDLE AGED; PYRAZOLES; PYRIDONES; YOUNG ADULT;

EID: 84928312539     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/bcp.12541     Document Type: Article

References (53)

1. Kaiser B,. Factor Xa-a promising target for drug development. Cell Mol Life Sci 2002; 59: 189-192.
2. Pinto DJ, Orwat MJ, Koch S, Rossi KA, Alexander RS, Smallwood A, Wong PC, Rendina AR, Luettgen JM, Knabb RM, He K, Xin B, Wexler RR, Lam PY,. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 2007; 50: 5339-5356.
3. Wong PC, Crain EJ, Xin B, Wexler RR, Lam PY, Pinto DJ, Luettgen JM, Knabb RM,. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 6: 820-829.
4. Connolly SJ, Eikelboom J, Joyner C, Diener HC, 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 KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S,. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
5. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek E, 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 S, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon J, Pais P, Parkhomenko A, Verheugt F, Zhu J, Wallentin L,. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
6. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ,. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604.
7. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P,. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-815.
8. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM,. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363: 2487-2498.
9. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI,. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799-808.
10. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz J,. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368: 699-708.
11. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G,. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-88S.
12. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G,. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 160S-198.
13. Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, Yu Z, Shenker A, Barrett YC, Mosqueda-Garcia R, LaCreta F,. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 2013; 76: 776-786.
14. Frost C, Wang J, Nepal S, Schuster A, Barrett YC, Mosqueda-Garcia R, Reeves RA, LaCreta F,. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 2013; 75: 476-487.
15. Frost C, Yu Z, Nepal S, Bragat A, Moore K, Shenker A, Barrett YC, LaCreta F,. Apixaban, a direct factor Xa inhibitor: single-dose pharmacokinetics and pharmacodynamics of an intravenous formulation [abstract]. J Clin Pharmacol 2008; 48: 1132.
16. Vakkalagadda B, Frost C, Wang J, Nepal S, Schuster A, Zhang D, Dias C, Yu Z, Shenker A, LaCreta F,. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa [abstract]. J Clin Pharmacol 2009; 49: 1091-1130.
17. Zhang D, He K, Herbst JJ, Kolb J, Shou W, Wang L, Balimane P, Han Y-H, Gan J, Frost CE,. Characterization of transporters involved in distribution and disposition of apixaban. Drug Metab Dispos 2013; 41: 827-835.
18. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L,. Membrane transporters in drug development. Nat Rev Drug Discov 2010; 9: 215-236.
19. Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, Pinto D, Chen S, Bonacorsi S, Wong PC, Zhang D,. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37: 74-81.
20. Wang L, Zhang D, Raghavan N, Yao M, Ma L, Frost CE, Maxwell BD, Chen SY, He K, Goosen TC, Humphreys WG, Grossman SJ,. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos 2010; 38: 448-458.
21. Wang L, He K, Maxwell B, Grossman SJ, Tremaine LM, Humphreys WG, Zhang D,. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos 2011; 39: 256-264.
22. Wang X, Tirucherai G, Pannacciulli N, Wang J, Elsrougy A, Teslenko V, Chang M, Zhang D, Frost C,. Effect of activated charcoal on the pharmacokinetics of apixaban in healthy subjects. ASCPT 2012. 15-3-2012.
23. Zhang D, He K, Raghavan N, Wang L, Mitroka J, Maxwell BD, Knabb RM, Frost C, Schuster A, Hao F, Gu Z, Humphreys WG, Grossman SJ,. Comparative metabolism of 14C-labeled apixaban in mice, rats, rabbits, dogs, and humans. Drug Metab Dispos 2009; 37: 1738-1748.
24. Wang L, Raghavan N, He K, Luettgen JM, Humphreys WG, Knabb RM, Pinto DJ, Zhang D,. Sulfation of o-demethyl apixaban: enzyme identification and species comparison. Drug Metab Dispos 2009; 37: 802-808.
25. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC,. The human intestinal cytochrome P450 'pie'. Drug Metab Dispos 2006; 34: 880-886.
26. Rostami-Hodjegan A, Tucker GT,. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 2007; 6: 140-148.
27. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP,. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414-423.
28. Aithal GP, Day CP, Kesteven PJ, Daly AK,. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-719.
29. Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM,. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos 2002; 30: 869-874.
30. Nebert DW, Russell DW,. Clinical importance of the cytochromes P450. Lancet 2002; 360: 1155-1162.
31. Plastaras JP, Guengerich FP, Nebert DW, Marnett LJ,. Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde. J Biol Chem 2000; 275: 11784-11790.
32. Bailey DG, Malcolm J, Arnold O, Spence JD,. Grapefruit juice-drug interactions. Br J Clin Pharmacol 1998; 46: 101-110.
33. Durr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K,. St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 2000; 68: 598-604.
34. Roby CA, Anderson GD, Kantor E, Dryer DA, Burstein AH,. St John's Wort: effect on CYP3A4 activity. Clin Pharmacol Ther 2000; 67: 451-457.
35. Edgar B, Bailey D, Bergstrand R, Johnsson G, Regardh CG,. Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine-and its potential clinical relevance. Eur J Clin Pharmacol 1992; 42: 313-317.
36. Nappi JM,. Warfarin and phenytoin interaction. Ann Intern Med 1979; 90: 852.
37. Shenfield GM, Page M,. Potentiation of warfarin action by miconazole oral gel. Aust N Z J Med 1991; 21: 928.
38. Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ,. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004; 57: 592-599.
39. Benet LZ, Cummins CL,. The drug efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 2001; 50 (Suppl. 1): S3-11.
40. University of Washington. Metabolism and transport drug interaction database. Available at http://www.druginteractioninfo.org (last accessed February 2012).
41. Food and Drug Administration. Guidance for industry. Drug interaction studies-study design, data analysis and implications for dosing and labeling. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf (last accessed February 2013).
42. Rowland YK, Jamei M, Yang J, Tucker GT, Rostami-Hodjegan A,. Physiologically based mechanistic modelling to predict complex drug-drug interactions involving simultaneous competitive and time-dependent enzyme inhibition by parent compound and its metabolite in both liver and gut-the effect of diltiazem on the time-course of exposure to triazolam. Eur J Pharm Sci 2010; 39: 298-309.
43. Cornwell MM, Pastan I, Gottesman MM,. Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J Biol Chem 1987; 262: 2166-2170.
44. Jones DR, Gorski JC, Hamman MA, Mayhew BS, Rider S, Hall SD,. Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite intermediate complex formation. J Pharmacol Exp Ther 1999; 290: 1116-1125.
45. Pursley J, Shen JX, Schuster A, Dang OT, Lehman J, Buonarati MH, Song Y, Aubry A-F, Arnold ME,. LC-MS/MS determination of apixaban (BMS562247) and its major metabolite in human plasma-an application of polarity switching and monolithic HPLC column. Bioanalysis 2014; 6: 2071-2082.
46. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G, McLeod J, Obach RS, Roberts S, Roe A, Shah A, Snikeris F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA,. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 2003; 31: 815-832.
47. Stoch SA, Friedman E, Maes A, Yee K, Xu Y, Larson P, Fitzgerald M, Chodakewitz J, Wagner JA,. Effect of different durations of ketoconazole dosing on the single-dose pharmacokinetics of midazolam: shortening the paradigm. J Clin Pharmacol 2009; 49: 398-406.
48. Daneshmend TK, Warnock DW,. Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet 1988; 14: 13-34.
49. Sista S, Lai JC, Eradiri O, Albert KS,. Pharmacokinetics of a novel diltiazem HCl extended-release tablet formulation for evening administration. J Clin Pharmacol 2003; 43: 1149-1157.
50. Chung E, Nafziger AN, Kazierad DJ, Bertino JS, Jr,. Comparison of midazolam and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther 2006; 79: 350-361.
51. Olkkola KT, Backman JT, Neuvonen PJ,. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 1994; 55: 481-485.
52. Bristol-Myers Squibb and Pfizer EEIG. Eliquis® (apixaban tablets) Summary of product characteristics. Available at http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/002148/WC500107728.pdf (last accessed January 2013).
53. Bristol-Myers Squibb Company. Eliquis® (apixaban tablets) Prescribing Information. Available at http://www.accessdata.fda.gov/drugsatfda-docs/label/2012/202155s000lbl.pdf (last accessed January 2013).