Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of Prasugrel

Clinical Pharmacokinetics

Volumn 49, Issue 12, 2010, Pages 777-798

  Small, David S ^a   Farid, Nagy A ^a   Payne, Christopher D ^a   Konkoy, Christopher S ^a   Jakubowski, Joseph A ^a   Winters, Kenneth J ^a   Salazar, Daniel E ^b  

^a ELI LILLY AND COMPANY   (United States)

^b DAIICHI SANKYO INC   (United States)

Author keywords

Antiplatelets, pharmacodynamics; Antiplatelets, pharmacokinetics; Antithrombotics, pharmacodynamics; Antithrombotics, pharmacokinetics; Drug interactions; Metabolites; Pharmacokinetic pharmacodynamic relationships; Prasugrel, pharmacodynamics; Prasugrel, pharmacokinetics; Research and development

Indexed keywords

ACETYLSALICYLIC ACID; AMFEBUTAMONE; ATORVASTATIN; CIPROFLOXACIN; CLARITHROMYCIN; CLOPIDOGREL; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C8; DIGOXIN; DILTIAZEM; DRUG METABOLITE; EFFIENT; EFIENT; HEPARIN; INDINAVIR; KETOCONAZOLE; LANSOPRAZOLE; METOPROLOL; MEVINOLIN; PRASUGREL; R 106583; R 119251; R 138727; R 95913; RANITIDINE; RIFAMPICIN; SIMVASTATIN; TICLOPIDINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERAPAMIL; WARFARIN;

ACUTE CORONARY SYNDROME; AGE; ALLELE; AREA UNDER THE CURVE; ARTERY DISEASE; ATHEROSCLEROSIS; BARE METAL STENT; BLEEDING; BLOOD TOXICITY; BODY WEIGHT; CAUCASIAN; CLINICAL PHARMACOLOGY; CLINICAL TRIAL; COMPETITIVE INHIBITION; CONGESTIVE HEART FAILURE; CORONARY STENT; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE REGIMEN; DRUG ELUTING STENT; DRUG HALF LIFE; DRUG HYDROLYSIS; DRUG METABOLISM; DRUG POTENTIATION; DRUG STRUCTURE; DRUG TOLERABILITY; ETHNICITY; FOOD; GENETIC VARIABILITY; HEART DEATH; HEART INFARCTION; HUMAN; INTESTINE; ISCHEMIA; KIDNEY DISEASE; KIDNEY DYSFUNCTION; LIVER; LIVER DISEASE; LOADING DRUG DOSE; MAXIMUM PLASMA CONCENTRATION; MONOTHERAPY; NON ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; PERCUTANEOUS CORONARY INTERVENTION; PHARMACODYNAMICS; PRIORITY JOURNAL; REVIEW; SINGLE DRUG DOSE; SMOKING; STENT THROMBOSIS; STEREOISOMERISM; STOMACH ACID; STROKE; THROMBOCYTE AGGREGATION; THROMBOSIS; TREATMENT RESPONSE; UNSTABLE ANGINA PECTORIS;

ACUTE CORONARY SYNDROME; ANGIOPLASTY, BALLOON, CORONARY; DRUG INTERACTIONS; HUMANS; PIPERAZINES; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PURINERGIC P2Y RECEPTOR ANTAGONISTS; THIOPHENES;

EID: 78349232464     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.2165/11537820-000000000-00000     Document Type: Review

References (103)

1. Talbert RL. Overview of advances in cardiovascular disease treatment and prevention: the evolving role of antiplatelet therapy. Am J Health Syst Pharm 2008 Jul 1; 65 (13 Suppl. 5): S1-5
2. King III SB, Smith Jr SC, Hirshfeld Jr JW, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, writing on behalf of the 2005 Writing Committee [published erratum appears in Circulation 2008 Feb 12; 117 (6): e161]. Circulation 2008 Jan 15; 117 (2): 261-95
3. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications,management, and future perspectives. J Am Coll Cardiol 2007 Apr 10; 49 (14): 1505-16
4. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients [published erratum appears in BMJ 2002 Jan 19; 324 (7330): 141]. BMJ 2002 Jan 12; 324 (7329): 71-6
5. Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: current status and future directions. Thromb Haemost 2009 Jul; 102 (1): 7-14
6. Emmons KL, Taylor NR. Contemporary issues in clopidogrel therapy: new evidence shaping clinical practice. Pharmacotherapy 2007 Apr; 27 (4): 553-63
7. Smyth SS, Woulfe DS, Weitz JI, et al. G-protein-coupled receptors as signaling targets for antiplatelet therapy. Aterioscler Thromb Vasc Biol 2009 Apr; 29 (4): 449-57
8. Jakubowski JA, Winters KJ, Naganuma H, et al. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev 2007 Winter; 25 (4): 357-74
9. Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronaryartery stents. N Engl J Med 1996 Apr 25; 334 (17): 1084-9
10. Eshaghian S, Kaul S, Amin S, et al. Role of clopidogrel in managing atherothrombotic cardiovascular disease. Ann InternMed 2007Mar 20; 146 (6): 434-41
11. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996 Nov 16; 348 (9038): 1329-39
12. Yusuf S, Zhao F,Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation [published errata appear in N Engl J Med 2001 Dec 6; 345 (23): 1716] N Engl J Med 2001 Nov 15; 345 (20): 1506].
13. N Engl J Med 2001 Aug 16; 345 (7): 494-502
14. Steinhubl SR, Berger PB, Mann III JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial [published erratum appears in JAMA 2003 Feb 26; 289 (8): 987] JAMA 2002 Nov 20; 288 (19): 2411-20
15. Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCICLARITY study. JAMA 2005 Sep 14; 294 (10): 1224-32
16. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebocontrolled trial. Lancet 2005 Nov 5; 366 (9497): 1607-21
17. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010 Mar 16; 121 (10): 1188-99
18. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004 Jun 29; 109 (25): 3171-5
19. Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006 Mar; 4 (3): 542-9
20. Gurbel PA, Tantry US. Drug insight: clopidogrel nonresponsiveness. Nat Clin Pract Cardiovasc Med 2006 Jul; 3 (7): 387-95
21. Hochholzer W, Trenk D, Bestehorn HP, et al. Impact of the degree of periinterventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006 Nov 7; 48 (9): 1742-50
22. Sweeny JM, Gorog DA, Fuster V. Antiplatelet drug 'resistance': part 1. Mechanisms and clinical measurements. Nat Rev Cardiol 2009 Apr; 6 (4): 273-82
23. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007 Nov 15; 357 (20): 2001-15 (Pubitemid 350106708)
24. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics: 2009 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009 Jan 27; 119 (3): 480-6
25. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008 Apr 19; 371 (9621): 1353-63
26. Salazar DE, Ernest II CS,Wrishko RE, et al. Relationship between exposure to the prasugrel active metabolite with TIMI major/minor bleeding in TRITONTIMI 38 [abstract no. 4001]. Circulation 2008; 118 (18 Suppl. 2): S815
27. Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel- Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 2008 May 27; 51 (21): 2028-33
28. Bhatt DL. Intensifying platelet inhibition: navigating between Scylla and Charybdis. N Engl J Med 2007 Nov 15; 357 (20): 2078-81
29. Harrison P, Frelinger III AL, Furman MI, et al. Measuring antiplatelet drug effects in the laboratory. Thromb Res 2007; 120 (3): 323-36
30. Michelson AD, Frelinger III AL, Furman MI. Current options in platelet function testing. Am J Cardiol 2006 Nov 20; 98 (10 Suppl. 1): S4-10
31. Horstrup K, Jablonka B, Hönig-Liedl P, et al. Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at Ser157 in intact human platelets correlates with fibrinogen receptor inhibition. Eur J Biochem 1994 Oct 1; 225 (1): 21-7 (Pubitemid 24306224)
32. Jakubowski JA, Payne CD, Li YG, et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASPphosphorylation and light transmission aggregometry. Thromb Haemost 2008 Jan; 99 (1): 215-22
33. Jakubowski JA, Payne CD, Li YG, et al. The use of the VerifyNow P2Y12 point of care device to monitor platelet function across a range of P2Y12 inhibition levels following prasugrel and clopidogrel administration. Thromb Haemost 2008 Feb; 99 (2): 409-15
34. Payne CD, Li YG, Small DS, et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007 Nov; 50 (5): 555-62
35. Farid NA, Kurihara A, Wrighton SA. The metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol 2010 Feb; 50 (2): 126-42
36. Jakubowski JA, Payne CD, Weerakkody GJ, et al. Dose-dependent inhibition of human platelet aggregation by prasugrel and its interaction with aspirin in healthy subjects. J Cardiovasc Pharmacol 2007 Mar; 49 (3): 167-73
37. Payne CD, Li YG, Brandt JT, et al. Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirintreated subjects. Platelets 2008 Jun; 19 (4): 275-8179
38. Small DS, Farid NA, Li YG, et al. Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. CurrMed Res Opin 2008 Aug; 24 (8): 2251-7
39. Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008 Apr; 48 (4): 475-84
40. Farid NA, Payne CD, Small DS, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 2007 May; 81 (5): 735-41
41. Farid NA, Payne CD, Ernest CS, et al. Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol 2008 Jan; 48(1): 53-9
42. Farid NA, Jakubowski JA, Payne CD, et al. Effect of rifampin on the pharmacokinetics and pharmacodynamics of prasugrel in healthy male subjects. Curr Med Res Opin 2009 Aug; 25 (8): 1821-9
43. Farid N, Small D, Payne C, et al. Effects of atorvastatin on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in healthy subjects. Pharmacother 2008; 28 (12): 1483-94
44. Eli Lilly and Company. Clinical study summary: study H7T-EW-TAAT. The effect of prasugrel on the pharmacodynamic response of unfractionated heparin in healthy subjects [CT registry ID# 8977; online]. Available from URL: http://www.clinicalstudyresults.org/documents/company-study-8937-0.pdf [Accessed 2010 Sep 8]
45. Eli Lilly and Company. Clinical study summary: study H7T-EW-TAAR. The effect of prasugrel on the pharmacodynamics and pharmacokinetics of single dose warfarin in healthy subjects [CT registry ID# 8975; online]. Available fromURL: http://www.clinicalstudyresults.org/documents/company-study-8935-0.pdf [Accessed 2010 Sep 8]
46. Eli Lilly and Company. Clinical study summary: study H7T-EW-TAAX. The effect of prasugrel on the disposition of digoxin in healthy subjects [CT registry ID# 8982; online]. Available from URL: http://www.clinicalstudyresults. org/documents/company-study-8942-0.pdf [Accessed 2010 Sep 8]
47. Williams ET, Jones KO, Ponsler GD, et al. The biotransformation of prasugrel, a new thienopyridine prodrug, by the human carboxylesterases 1 and 2. Drug Metab Dispos 2008 Jul; 36 (7): 1227-32
48. Rehmel JL, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006 Apr; 34 (4): 600-7
49. Hagihara K, Kurihara A, Kawai K, et al. Absorption, distribution and excretion of the new thienopyridine agent prasugrel in rats. Xenobiotica 2007 Jul; 37 (7): 788-801
50. Smith RL, Gillespie TA, Rash TJ, et al. Disposition and metabolic fate of prasugrel in mice, rats, and dogs. Xenobiotica 2007 Aug; 37 (8): 884-901
51. Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos 2007 Jul; 35 (7): 1096-104
52. Farid NA, McIntosh M, Garofolo F, et al. Determination of the active and inactive metabolites of prasugrel in human plasma by liquid chromatography/ tandem mass spectrometry. Rapid Commun Mass Spectrom 2007; 21 (2): 169-79
53. Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007 Jan; 153 (1): 66.e9-16
54. Efient 5 mg film-coated tablets: summary of product characteristics. Houten: Eli Lilly Nederland BV, 2009 Dec 2 [online]. Available from URL: http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/ human/000984/WC500021971.pdf [Accessed 2010 Sep 8]
55. Effient (prasugrel) tablets: US prescribing information. Indianapolis (IN): Eli Lilly and Company, 2009 Jul [online]. Available from URL: http://pi.lilly.com/us/effient.pdf [Accessed 2010 Sep 8]
56. Satoh T, Taylor P, Bosron WF, et al. Current progress on esterases: from molecular structure to function. DrugMetab Dispos 2002May; 30 (5): 488-93
57. Taketani M, Shii M, Ohura K, et al. Carboxylesterase in the liver and small intestine of experimental animals and human. Life Sci 2007 Aug 23; 81 (11): 924-32
58. Paine MF, Hart HL, Ludington SS, et al. The human intestinal cytochrome P450 'pie'. Drug Metab Dispos 2006 May; 34 (5): 880-6
59. Eli Lilly and Company. Clinical study summary: study H7T-EW-TAAJ. An investigation into the inhibition of platelet aggregation following administration of clopidogrel and CS-747 at anticipated loading doses [CT registry ID# 8391; online]. Available from URL: http://www.clinicalstudyresults. org/documents/company-study-8929-0.pdf [Accessed 2010 Sep 8]
60. Ernest II CS, Small DS, Rohatagi S, et al. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease. J Pharmacokinet Pharmacodyn 2008 Dec; 35 (6): 593-618
61. Eli Lilly and Company. Clinical study summary: study H7T-EW-TAAD. A pharmacokinetic and pharmacodynamic comparison of CS-747 (LY640315) versus clopidogrel in subjects with stable atherosclerosis [CT registry ID#6210; online]. Available from URL: http://www.clinicalstudyresults.org/documents/ company-study-8925-0.pdf [Accessed 2010 Sep 8]
62. Hasegawa M, Sugidachi A, Ogawa T, et al. Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747 (prasugrel, LY640315), a novel P2Y12 receptor inhibitor. Thromb Haemost 2005 Sep; 94 (3): 593-8
63. Kazui M, Hagihara K, Farid NA, et al. Stereoselectivity of thiol s-methyl transferase responsible for the methylation of the active metabolite of prasugrel [abstract]. Drug Metab Rev 2008; 40 Suppl. 3: 101
64. Prasugrel NDA, section 2.7.2: summary of clinical pharmacology. Indianapolis (IN): Eli Lilly and Company, 2007. (Data on file)
65. Takahashi M, Kawabata K, Kurihara A, et al. Chiral inversion and enantioselective active metabolite formation of prasugrel, a novel thienopyridine antiplatelet agent, in dogs. Drug Metab Rev 2006; 38 Suppl. 2: 88-9
66. Wickremsinhe ER, Tian Y, Ruterbories KJ, et al. Stereoselective metabolism of prasugrel in humans using a novel chiral liquid chromatography-tandem mass spectrometry method. Drug Metab Dispos 2007 Jun; 35 (6): 917-21
67. Small DS, Farid NA, Payne CD, et al. Prasugrel 60 mg and clopidogrel 300 mg loading doses: a pharmacokinetic basis for the observed difference in platelet aggregation response [abstract]. Am J Cardiol 2006; 98 (8 Suppl. 1): 200M
68. Jakubowski JA, Sugidachi A, Ogawa T, et al. Comparative antiplatelet effects of the active metabolites of CS-747 (prasugrel, LY640315) and clopidogrel. J Thromb Haemost 2005; 3 Suppl. 1: P2299
69. Sugidachi A, Ogawa T, Kurihara A, et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite [published erratum appears in J Thromb Haemost 2007 Sep; 5 (9): 1995] J Thromb Haemost 2007 Jul; 5 (7): 1545-51
70. Wrishko RE, Ernest II CS, Small DS, et al. Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38. J Clin Pharmacol 2009 Aug; 49 (8): 984-98
71. Li YG, Ni L, Brandt JT, et al. Inhibition of platelet aggregation with prasugrel and clopidogrel: an integrated analysis in 846 subjects. Platelets 2009 Aug; 20 (5): 316-27
72. Small DS,Wrishko RE, Ernest IICS, et al. Effect of age on the pharmacokinetics and pharmacodynamics of prasugrel duringmultiple dosing. DrugsAging 2009; 26 (9): 781-90
73. Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP 2C19 andCYP 2C9 affect the pharmacodynamic and pharmacokinetic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5 (12): 2429-36
74. Kirkwood S, McCorkle K, Walker J, et al. Prasugrel and clopidogrel in Chinese CYP2C19 allelic variants following maintenance doses [abstract no. AS-248]. Am J Cardiol 2009 Apr 22; 103 (9 Suppl. 1): 105B
75. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009 May 19; 119 (19): 3553-60
76. Varenhorst C, James S, Erlinge D, et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur Heart J 2009 Jul; 30 (14): 1744-52
77. Eli Lilly and Company. Clinical study summary: study H7T-FW-TAAQ. A study to evaluate the safety and tolerability of prasugrel in healthy Chinese subjects, and to compare effects of prasugrel and clopidogrel in Chinese and Caucasian subjects [CT registry ID# 8973; online]. Available from URL:http://www.clinicalstudyresults.org/documents/company-study-8934-0.pdf [Accessed 2010 Sep 8]
78. Small DS, Payne CD, Kothare P, et al. Pharmacodynamics and pharmacokinetics of single doses of prasugrel 30 mg and clopidogrel 300 mg in healthy Chinese andWhite volunteers: an open-label trial. ClinTher 2010; 32 (2): 365-79
79. Small DS, Kothare P, Yuen E, et al. The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects. Eur J Clin Pharmacol 2010; 66 (2): 127-35
80. Small DS, Farid NA, Li YG, et al. Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver disease. J Clin Pharm Ther 2009 Oct; 34 (5): 575-83
81. Small DS, Wrishko RE, Ernest II CS, et al. Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and endstage renal disease. J Clin Pharm Ther 2009 Oct; 34 (5): 585-94
82. Boldt J, Hüttner I, Suttner S, et al. Changes of haemostasis in patients undergoing major abdominal surgery: is there a difference between elderly and younger patients? Br J Anaesth 2001 Sep; 87 (3): 435-40
83. Small DS, Li YG, Ernest CS II, et al. Integrated analysis of pharmacokinetic data across multiple clinical pharmacology studies of prasugrel, a new thienopyridine antiplatelet agent. J Clin Pharmacol. Epub 2010 Apr 21
84. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973 Aug; 60 (8) 646-9
85. Eli Lilly and Company. Clinical study summary: study H7T-EW-TAAF. Comparative bioavailability assessment of CS-747.base andCS-747.HCl with a pilot CS-747.HCl food effect assessment in healthy subjects [CT registry ID# 6056; online]. Available from URL: http://www.clinicalstudyresults.org/documents/ company-study-8922-0.pdf [Accessed 2010 Sep 8]
86. Eli Lilly and Company. Study H7T-EW-TACT. Effect of food on the bioavailability of stored prasugrel tablets after a single 60-mg prasugrel dose and a single 10-mg dose in healthy subjects. Indianapolis (IN): Eli Lilly and Company, 2008. (Data on file)
87. Wiviott SD, Antman EM, Gibson CM, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes.AmHeart J 2006; 152 (4): 627-35
88. Center for Drug Evaluation and Research, US FDA. Approval package for Plavix [application no. 20839]: clinical pharmacology and biopharmaceutics review. Rockville (MD): FDA, 1997 Oct 15: 92 [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda-docs/nda/pre96/020839-s000.pdf [Accessed 2010 Oct 15]
89. Common technical document, summary of clinical pharmacology, appendix 2.7.2.5. Indianapolis (IN): Eli Lilly and Company, 2007. (Data on file)
90. Eli Lilly and Company. Clinical study summary: study H7T-EW-TAAU. A study to assess the pharmacodynamic interaction between aspirin and prasugrel in healthy subjects [CT registry ID# 8978; online]. Available from URL: http://www.clinicalstudyresults.org/documents/company-study-8938-0.pdf [Accessed 2010 Sep 8]
91. Park JE, Kim KB, Bae SK, et al. Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin. Xenobiotica 2008 Sep; 38 (9): 1240-51
92. NiemiM, Backman JT, Fromm MF, et al. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet 2003; 42 (9): 819-50
93. Rettie AE, Korzekwa KR, Kunze KL, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992 Jan-Feb; 5 (1): 54-9
94. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73 (1): 67-74
95. Bauman JL, Didomenico RJ, Galanter WL. Mechanisms, manifestations, and management of digoxin toxicity in the modern era. Am J Cardiovasc Drugs 2006; 6 (2): 77-86
96. Fenner KS, TroutmanMD, Kempshall S, et al. Drug-drug interactionsmediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug. Clin Pharmacol Ther 2009 Feb; 85 (2): 173-81
97. Tanigawara Y, Okamura N, Hirai M, et al. Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J Pharmacol Exp Ther 1992 Nov; 263 (2): 840-5
98. Okamura N, Hirai M, Tanigawara Y, et al. Digoxin-cyclosporin A interaction: modulation of the multidrug transporter P-glycoprotein in the kidney. J Pharmacol Exp Ther 1993 Sep; 266 (3): 1614-9
99. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading and maintenance-dose clopidogrel in patients with planned percutaneous intervention. Circulation 2007 Dec 18; 116 (25): 2923-32
100. Richter T, Mürdter TE, Heinkele G, et al. Potentmechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther 2004 Jan; 308 (1): 189-97
101. Turpeinen M, Tolonen A, Uusitalo J, et al. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther 2005 Jun; 77 (6): 553-9
102. Faucette SR, Hawke RL, Lecluyse EL, et al. Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 2000 Oct; 28 (10): 1222-30
103. Hesse LM, Venkatakrishnan K, Court MH, et al. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 2000 Oct; 28 (10): 1176-83