Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor
Aim Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non‐renal elimination. Non‐renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two...
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| Published in | British journal of clinical pharmacology Vol. 79; no. 5; pp. 838 - 846 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
BlackWell Publishing Ltd
01.05.2015
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Aim
Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non‐renal elimination. Non‐renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two single sequence studies evaluated the effect of ketoconazole (a strong dual inhibitor of CYP3A4 and P‐glycoprotein [P‐gp]) and diltiazem (a moderate CYP3A4 inhibitor and a P‐gp inhibitor) on apixaban pharmacokinetics in healthy subjects.
Method
In the ketoconazole study, 18 subjects received apixaban 10 mg on days 1 and 7, and ketoconazole 400 mg once daily on days 4–9. In the diltiazem study, 18 subjects received apixaban 10 mg on days 1 and 11 and diltiazem 360 mg once daily on days 4–13.
Results
Apixaban maximum plasma concentration and area under the plasma concentration–time curve extrapolated to infinity increased by 62% (90% confidence interval [CI], 47, 78%) and 99% (90% CI, 81, 118%), respectively, with co‐administration of ketoconazole, and by 31% (90% CI, 16, 49%) and 40% (90% CI, 23, 59%), respectively, with diltiazem.
Conclusion
A 2‐fold and 1.4‐fold increase in apixaban exposure was observed with co‐administration of ketoconazole and diltiazem, respectively. |
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| AbstractList | Aim
Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non‐renal elimination. Non‐renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two single sequence studies evaluated the effect of ketoconazole (a strong dual inhibitor of CYP3A4 and P‐glycoprotein [P‐gp]) and diltiazem (a moderate CYP3A4 inhibitor and a P‐gp inhibitor) on apixaban pharmacokinetics in healthy subjects.
Method
In the ketoconazole study, 18 subjects received apixaban 10 mg on days 1 and 7, and ketoconazole 400 mg once daily on days 4–9. In the diltiazem study, 18 subjects received apixaban 10 mg on days 1 and 11 and diltiazem 360 mg once daily on days 4–13.
Results
Apixaban maximum plasma concentration and area under the plasma concentration–time curve extrapolated to infinity increased by 62% (90% confidence interval [CI], 47, 78%) and 99% (90% CI, 81, 118%), respectively, with co‐administration of ketoconazole, and by 31% (90% CI, 16, 49%) and 40% (90% CI, 23, 59%), respectively, with diltiazem.
Conclusion
A 2‐fold and 1.4‐fold increase in apixaban exposure was observed with co‐administration of ketoconazole and diltiazem, respectively. Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non-renal elimination. Non-renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two single sequence studies evaluated the effect of ketoconazole (a strong dual inhibitor of CYP3A4 and P-glycoprotein [P-gp]) and diltiazem (a moderate CYP3A4 inhibitor and a P-gp inhibitor) on apixaban pharmacokinetics in healthy subjects. In the ketoconazole study, 18 subjects received apixaban 10 mg on days 1 and 7, and ketoconazole 400 mg once daily on days 4-9. In the diltiazem study, 18 subjects received apixaban 10 mg on days 1 and 11 and diltiazem 360 mg once daily on days 4-13. Apixaban maximum plasma concentration and area under the plasma concentration-time curve extrapolated to infinity increased by 62% (90% confidence interval [CI], 47, 78%) and 99% (90% CI, 81, 118%), respectively, with co-administration of ketoconazole, and by 31% (90% CI, 16, 49%) and 40% (90% CI, 23, 59%), respectively, with diltiazem. A 2-fold and 1.4-fold increase in apixaban exposure was observed with co-administration of ketoconazole and diltiazem, respectively. Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non-renal elimination. Non-renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two single sequence studies evaluated the effect of ketoconazole (a strong dual inhibitor of CYP3A4 and P-glycoprotein [P-gp]) and diltiazem (a moderate CYP3A4 inhibitor and a P-gp inhibitor) on apixaban pharmacokinetics in healthy subjects.AIMApixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non-renal elimination. Non-renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two single sequence studies evaluated the effect of ketoconazole (a strong dual inhibitor of CYP3A4 and P-glycoprotein [P-gp]) and diltiazem (a moderate CYP3A4 inhibitor and a P-gp inhibitor) on apixaban pharmacokinetics in healthy subjects.In the ketoconazole study, 18 subjects received apixaban 10 mg on days 1 and 7, and ketoconazole 400 mg once daily on days 4-9. In the diltiazem study, 18 subjects received apixaban 10 mg on days 1 and 11 and diltiazem 360 mg once daily on days 4-13.METHODIn the ketoconazole study, 18 subjects received apixaban 10 mg on days 1 and 7, and ketoconazole 400 mg once daily on days 4-9. In the diltiazem study, 18 subjects received apixaban 10 mg on days 1 and 11 and diltiazem 360 mg once daily on days 4-13.Apixaban maximum plasma concentration and area under the plasma concentration-time curve extrapolated to infinity increased by 62% (90% confidence interval [CI], 47, 78%) and 99% (90% CI, 81, 118%), respectively, with co-administration of ketoconazole, and by 31% (90% CI, 16, 49%) and 40% (90% CI, 23, 59%), respectively, with diltiazem.RESULTSApixaban maximum plasma concentration and area under the plasma concentration-time curve extrapolated to infinity increased by 62% (90% confidence interval [CI], 47, 78%) and 99% (90% CI, 81, 118%), respectively, with co-administration of ketoconazole, and by 31% (90% CI, 16, 49%) and 40% (90% CI, 23, 59%), respectively, with diltiazem.A 2-fold and 1.4-fold increase in apixaban exposure was observed with co-administration of ketoconazole and diltiazem, respectively.CONCLUSIONA 2-fold and 1.4-fold increase in apixaban exposure was observed with co-administration of ketoconazole and diltiazem, respectively. |
| Author | Dias, Clapton Song, Yan Yu, Zhigang Boyd, Rebecca A. Zhang, Donglu Byon, Wonkyung Frost, Charles E. Schuster, Alan E. Shenker, Andrew Wang, Jessie LaCreta, Frank |
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| Keywords | anticoagulants CYP3A4 inhibitors drug-drug interactions P-glycoprotein inhibitors apixaban |
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| References | 1987; 262 2012; 141 2002; 59 2001; 50 2010; 38 2012 2006; 34 2002; 30 1994; 270 2006; 79 2000; 67 2000; 68 2010; 39 2013; 369 1988; 14 2013; 368 1999; 290 2013; 41 2010; 363 1979; 90 2007; 50 2008; 6 2000; 275 2011; 39 2009; 49 2003; 31 1998; 46 2013; 76 2002; 360 1991; 21 2013; 75 2004; 57 2010; 375 2008; 48 1994; 55 2007; 6 2009; 361 1999; 353 1992; 42 2008; 133 2014; 6 2011; 365 2011; 364 2009; 37 2003; 43 2010; 9 19657123 - N Engl J Med. 2009 Aug 6;361(6):594-604 21071521 - Drug Metab Dispos. 2011 Feb;39(2):256-64 23382458 - Drug Metab Dispos. 2013 Apr;41(4):827-35 1818557 - Aust N Z J Med. 1991 Dec;21(6):928 3280211 - Clin Pharmacokinet. 1988 Jan;14(1):13-34 23216615 - N Engl J Med. 2013 Feb 21;368(8):699-708 8035341 - J Pharmacol Exp Ther. 1994 Jul;270(1):414-23 22315269 - Chest. 2012 Feb;141(2 Suppl):e44S-88S 11576692 - Adv Drug Deliv Rev. 2001 Oct 1;50 Suppl 1:S3-11 14517197 - J Clin Pharmacol. 2003 Oct;43(10):1149-57 20206776 - Lancet. 2010 Mar 6;375(9717):807-15 12387968 - Lancet. 2002 Oct 12;360(9340):1155-62 17268485 - Nat Rev Drug Discov. 2007 Feb;6(2):140-8 1577050 - Eur J Clin Pharmacol. 1992;42(3):313-7 19131519 - Drug Metab Dispos. 2009 Apr;37(4):802-8 17914785 - J Med Chem. 2007 Nov 1;50(22):5339-56 10454485 - J Pharmacol Exp Ther. 1999 Sep;290(3):1116-25 22759198 - Br J Clin Pharmacol. 2013 Feb;75(2):476-87 18315548 - J Thromb Haemost. 2008 May;6(5):820-9 20190787 - Nat Rev Drug Discov. 2010 Mar;9(3):215-36 21870978 - N Engl J Med. 2011 Sep 15;365(11):981-92 25322783 - Bioanalysis. 2014 Aug;6(15):2071-82 21309657 - N Engl J Med. 2011 Mar 3;364(9):806-17 20025966 - Eur J Pharm Sci. 2010 Mar 18;39(5):298-309 9723817 - Br J Clin Pharmacol. 1998 Aug;46(2):101-10 12814957 - Drug Metab Dispos. 2003 Jul;31(7):815-32 10824623 - Clin Pharmacol Ther. 2000 May;67(5):451-7 16580903 - Clin Pharmacol Ther. 2006 Apr;79(4):350-61 21175312 - N Engl J Med. 2010 Dec 23;363(26):2487-98 12124303 - Drug Metab Dispos. 2002 Aug;30(8):869-74 23451769 - Br J Clin Pharmacol. 2013 Nov;76(5):776-86 11180019 - Clin Pharmacol Ther. 2000 Dec;68(6):598-604 2434476 - J Biol Chem. 1987 Feb 15;262(5):2166-70 434697 - Ann Intern Med. 1979 May;90(5):852 16467132 - Drug Metab Dispos. 2006 May;34(5):880-6 11915937 - Cell Mol Life Sci. 2002 Feb;59(2):189-92 10766802 - J Biol Chem. 2000 Apr 21;275(16):11784-90 19246722 - J Clin Pharmacol. 2009 Apr;49(4):398-406 19420130 - Drug Metab Dispos. 2009 Aug;37(8):1738-48 15089812 - Br J Clin Pharmacol. 2004 May;57(5):592-9 10073515 - Lancet. 1999 Feb 27;353(9154):717-9 19940026 - Drug Metab Dispos. 2010 Mar;38(3):448-58 8181191 - Clin Pharmacol Ther. 1994 May;55(5):481-5 23808982 - N Engl J Med. 2013 Aug 29;369(9):799-808 18574265 - Chest. 2008 Jun;133(6 Suppl):160S-198S 18832478 - Drug Metab Dispos. 2009 Jan;37(1):74-81 |
| References_xml | – volume: 262 start-page: 2166 year: 1987 end-page: 2170 article-title: Certain calcium channel blockers bind specifically to multidrug‐resistant human KB carcinoma membrane vesicles and inhibit drug binding to P‐glycoprotein publication-title: J Biol Chem – volume: 360 start-page: 1155 year: 2002 end-page: 1162 article-title: Clinical importance of the cytochromes P450 publication-title: Lancet – volume: 21 start-page: 928 year: 1991 article-title: Potentiation of warfarin action by miconazole oral gel publication-title: Aust N Z J Med – volume: 55 start-page: 481 year: 1994 end-page: 485 article-title: Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole publication-title: Clin Pharmacol Ther – volume: 133 start-page: 160S year: 2008 end-page: 198 article-title: Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th Edition) publication-title: Chest – volume: 34 start-page: 880 year: 2006 end-page: 886 article-title: The human intestinal cytochrome P450 ‘pie’ publication-title: Drug Metab Dispos – volume: 290 start-page: 1116 year: 1999 end-page: 1125 article-title: Diltiazem inhibition of cytochrome P‐450 3A activity is due to metabolite intermediate complex formation publication-title: J Pharmacol Exp Ther – volume: 38 start-page: 448 year: 2010 end-page: 458 article-title: In vitro assessment of metabolic drug‐drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies publication-title: Drug Metab Dispos – volume: 49 start-page: 398 year: 2009 end-page: 406 article-title: Effect of different durations of ketoconazole dosing on the single‐dose pharmacokinetics of midazolam: shortening the paradigm publication-title: J Clin Pharmacol – volume: 43 start-page: 1149 year: 2003 end-page: 1157 article-title: Pharmacokinetics of a novel diltiazem HCl extended‐release tablet formulation for evening administration publication-title: J Clin Pharmacol – volume: 275 start-page: 11784 year: 2000 end-page: 11790 article-title: Xenobiotic‐metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde publication-title: J Biol Chem – volume: 37 start-page: 1738 year: 2009 end-page: 1748 article-title: Comparative metabolism of 14C‐labeled apixaban in mice, rats, rabbits, dogs, and humans publication-title: Drug Metab Dispos – year: 2012 article-title: Effect of activated charcoal on the pharmacokinetics of apixaban in healthy subjects – volume: 37 start-page: 74 year: 2009 end-page: 81 article-title: Apixaban metabolism and pharmacokinetics after oral administration to humans publication-title: Drug Metab Dispos – volume: 90 start-page: 852 year: 1979 article-title: Warfarin and phenytoin interaction publication-title: Ann Intern Med – volume: 68 start-page: 598 year: 2000 end-page: 604 article-title: St John's Wort induces intestinal P‐glycoprotein/MDR1 and intestinal and hepatic CYP3A4 publication-title: Clin Pharmacol Ther – volume: 6 start-page: 140 year: 2007 end-page: 148 article-title: Simulation and prediction of in vivo drug metabolism in human populations from data publication-title: Nat Rev Drug Discov – volume: 59 start-page: 189 year: 2002 end-page: 192 article-title: Factor Xa – a promising target for drug development publication-title: Cell Mol Life Sci – volume: 30 start-page: 869 year: 2002 end-page: 874 article-title: 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 publication-title: Drug Metab Dispos – volume: 6 start-page: 820 year: 2008 end-page: 829 article-title: Apixaban, an oral, direct and highly selective factor Xa inhibitor: , antithrombotic and antihemostatic studies publication-title: J Thromb Haemost – volume: 353 start-page: 717 year: 1999 end-page: 719 article-title: Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications publication-title: Lancet – volume: 14 start-page: 13 year: 1988 end-page: 34 article-title: Clinical pharmacokinetics of ketoconazole publication-title: Clin Pharmacokinet – volume: 368 start-page: 699 year: 2013 end-page: 708 article-title: Apixaban for extended treatment of venous thromboembolism publication-title: N Engl J Med – volume: 57 start-page: 592 year: 2004 end-page: 599 article-title: Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects publication-title: Br J Clin Pharmacol – volume: 365 start-page: 981 year: 2011 end-page: 992 article-title: Apixaban versus warfarin in patients with atrial fibrillation publication-title: N Engl J Med – volume: 375 start-page: 807 year: 2010 end-page: 815 article-title: Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE‐2): a randomised double‐blind trial publication-title: Lancet – volume: 6 start-page: 2071 year: 2014 end-page: 2082 article-title: LC‐MS/MS determination of apixaban (BMS562247) and its major metabolite in human plasma – an application of polarity switching and monolithic HPLC column publication-title: Bioanalysis – volume: 50 start-page: 5339 year: 2007 end-page: 5356 article-title: 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 publication-title: J Med Chem – volume: 369 start-page: 799 year: 2013 end-page: 808 article-title: Oral apixaban for the treatment of acute venous thromboembolism publication-title: N Engl J Med – volume: 49 start-page: 1091 year: 2009 end-page: 1130 article-title: Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa [abstract] publication-title: J Clin Pharmacol – volume: 141 start-page: e44S year: 2012 end-page: 88S article-title: Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines publication-title: Chest – volume: 46 start-page: 101 year: 1998 end-page: 110 article-title: Grapefruit juice–drug interactions publication-title: Br J Clin Pharmacol – volume: 9 start-page: 215 year: 2010 end-page: 236 article-title: Membrane transporters in drug development publication-title: Nat Rev Drug Discov – volume: 42 start-page: 313 year: 1992 end-page: 317 article-title: Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine – and its potential clinical relevance publication-title: Eur J Clin Pharmacol – volume: 76 start-page: 776 year: 2013 end-page: 786 article-title: Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects publication-title: Br J Clin Pharmacol – volume: 50 start-page: S3 issue: Suppl. 1 year: 2001 end-page: 11 article-title: The drug efflux‐metabolism alliance: biochemical aspects publication-title: Adv Drug Deliv Rev – volume: 364 start-page: 806 year: 2011 end-page: 817 article-title: Apixaban in patients with atrial fibrillation publication-title: N Engl J Med – volume: 31 start-page: 815 year: 2003 end-page: 832 article-title: The conduct of and drug–drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective publication-title: Drug Metab Dispos – volume: 39 start-page: 298 year: 2010 end-page: 309 article-title: 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 publication-title: Eur J Pharm Sci – volume: 75 start-page: 476 year: 2013 end-page: 487 article-title: Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects publication-title: Br J Clin Pharmacol – volume: 48 start-page: 1132 year: 2008 article-title: Apixaban, a direct factor Xa inhibitor: single‐dose pharmacokinetics and pharmacodynamics of an intravenous formulation [abstract] publication-title: J Clin Pharmacol – volume: 41 start-page: 827 year: 2013 end-page: 835 article-title: Characterization of transporters involved in distribution and disposition of apixaban publication-title: Drug Metab Dispos – volume: 270 start-page: 414 year: 1994 end-page: 423 article-title: 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 publication-title: J Pharmacol Exp Ther – volume: 363 start-page: 2487 year: 2010 end-page: 2498 article-title: Apixaban versus enoxaparin for thromboprophylaxis after hip replacement publication-title: N Engl J Med – volume: 79 start-page: 350 year: 2006 end-page: 361 article-title: Comparison of midazolam and simvastatin as cytochrome P450 3A probes publication-title: Clin Pharmacol Ther – volume: 39 start-page: 256 year: 2011 end-page: 264 article-title: Tissue distribution and elimination of [14C]apixaban in rats publication-title: Drug Metab Dispos – volume: 37 start-page: 802 year: 2009 end-page: 808 article-title: Sulfation of o‐demethyl apixaban: enzyme identification and species comparison publication-title: Drug Metab Dispos – volume: 361 start-page: 594 year: 2009 end-page: 604 article-title: Apixaban or enoxaparin for thromboprophylaxis after knee replacement publication-title: N Engl J Med – volume: 67 start-page: 451 year: 2000 end-page: 457 article-title: St John's Wort: effect on CYP3A4 activity publication-title: Clin Pharmacol Ther – reference: 25322783 - Bioanalysis. 2014 Aug;6(15):2071-82 – reference: 19657123 - N Engl J Med. 2009 Aug 6;361(6):594-604 – reference: 21870978 - N Engl J Med. 2011 Sep 15;365(11):981-92 – reference: 12124303 - Drug Metab Dispos. 2002 Aug;30(8):869-74 – reference: 18832478 - Drug Metab Dispos. 2009 Jan;37(1):74-81 – reference: 10454485 - J Pharmacol Exp Ther. 1999 Sep;290(3):1116-25 – reference: 1577050 - Eur J Clin Pharmacol. 1992;42(3):313-7 – reference: 11576692 - Adv Drug Deliv Rev. 2001 Oct 1;50 Suppl 1:S3-11 – reference: 3280211 - Clin Pharmacokinet. 1988 Jan;14(1):13-34 – reference: 19940026 - Drug Metab Dispos. 2010 Mar;38(3):448-58 – reference: 12814957 - Drug Metab Dispos. 2003 Jul;31(7):815-32 – reference: 16467132 - Drug Metab Dispos. 2006 May;34(5):880-6 – reference: 19246722 - J Clin Pharmacol. 2009 Apr;49(4):398-406 – reference: 15089812 - Br J Clin Pharmacol. 2004 May;57(5):592-9 – reference: 9723817 - Br J Clin Pharmacol. 1998 Aug;46(2):101-10 – reference: 10824623 - Clin Pharmacol Ther. 2000 May;67(5):451-7 – reference: 11915937 - Cell Mol Life Sci. 2002 Feb;59(2):189-92 – reference: 19420130 - Drug Metab Dispos. 2009 Aug;37(8):1738-48 – reference: 21175312 - N Engl J Med. 2010 Dec 23;363(26):2487-98 – reference: 22315269 - Chest. 2012 Feb;141(2 Suppl):e44S-88S – reference: 8181191 - Clin Pharmacol Ther. 1994 May;55(5):481-5 – reference: 434697 - Ann Intern Med. 1979 May;90(5):852 – reference: 23451769 - Br J Clin Pharmacol. 2013 Nov;76(5):776-86 – reference: 23382458 - Drug Metab Dispos. 2013 Apr;41(4):827-35 – reference: 23808982 - N Engl J Med. 2013 Aug 29;369(9):799-808 – reference: 8035341 - J Pharmacol Exp Ther. 1994 Jul;270(1):414-23 – reference: 11180019 - Clin Pharmacol Ther. 2000 Dec;68(6):598-604 – reference: 23216615 - N Engl J Med. 2013 Feb 21;368(8):699-708 – reference: 20190787 - Nat Rev Drug Discov. 2010 Mar;9(3):215-36 – reference: 17268485 - Nat Rev Drug Discov. 2007 Feb;6(2):140-8 – reference: 10766802 - J Biol Chem. 2000 Apr 21;275(16):11784-90 – reference: 20025966 - Eur J Pharm Sci. 2010 Mar 18;39(5):298-309 – reference: 12387968 - Lancet. 2002 Oct 12;360(9340):1155-62 – reference: 16580903 - Clin Pharmacol Ther. 2006 Apr;79(4):350-61 – reference: 17914785 - J Med Chem. 2007 Nov 1;50(22):5339-56 – reference: 1818557 - Aust N Z J Med. 1991 Dec;21(6):928 – reference: 10073515 - Lancet. 1999 Feb 27;353(9154):717-9 – reference: 2434476 - J Biol Chem. 1987 Feb 15;262(5):2166-70 – reference: 21071521 - Drug Metab Dispos. 2011 Feb;39(2):256-64 – reference: 22759198 - Br J Clin Pharmacol. 2013 Feb;75(2):476-87 – reference: 18315548 - J Thromb Haemost. 2008 May;6(5):820-9 – reference: 21309657 - N Engl J Med. 2011 Mar 3;364(9):806-17 – reference: 14517197 - J Clin Pharmacol. 2003 Oct;43(10):1149-57 – reference: 19131519 - Drug Metab Dispos. 2009 Apr;37(4):802-8 – reference: 18574265 - Chest. 2008 Jun;133(6 Suppl):160S-198S – reference: 20206776 - Lancet. 2010 Mar 6;375(9717):807-15 |
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Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non‐renal elimination.... Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non-renal elimination. Non-renal... |
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| SubjectTerms | Adolescent Adult anticoagulants apixaban Cross-Over Studies CYP3A4 inhibitors Cytochrome P-450 CYP3A - metabolism Cytochrome P-450 CYP3A Inhibitors - pharmacology Diltiazem - administration & dosage Diltiazem - pharmacology Dose-Response Relationship, Drug Drug Interactions drug–drug interactions Factor Xa Inhibitors - administration & dosage Factor Xa Inhibitors - blood Factor Xa Inhibitors - pharmacokinetics Factor Xa Inhibitors - pharmacology Female Healthy Volunteers Humans Ketoconazole - administration & dosage Ketoconazole - pharmacology Male Middle Aged Pyrazoles - administration & dosage Pyrazoles - blood Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Pyridones - administration & dosage Pyridones - blood Pyridones - pharmacokinetics Pyridones - pharmacology P‐glycoprotein inhibitors Young Adult |
| Title | Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor |
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