Abstract
Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of ‘parent’ ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1–2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration.
The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5′-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide.
Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total ezetimibe). Hence, ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of ezetimibe. Finally, higher ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.
Similar content being viewed by others
Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
References
Iglesias P, Diez JJ. New drags for the treatment of hypercholesterolemia. Expert Opin Investig Drags 2003; 12(11): 1777–89
Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol In Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285(19): 2486–97
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344 (8934): 1383–9
Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335(14): 1001–9
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998; 339 (19): 1349–5
Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333(20): 1301–7
Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study). JAMA 1998; 279(20): 1615–22
Collins R, Armitage J, Parish S, et al. MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361(9374): 2005–16
Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003; 92(2): 152–60
Foley KA, Simpson Jr RJ, Crouse III JR, et al. Effectiveness of statin titration on low-density lipoprotein cholesterol goal attainment in patients at high risk of atherogenic events. Am J Cardiol 2003; 92(1): 79–81
Hoerger TJ, Bala MV, Bray JW, et al. Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults. Am J Cardiol 1998; 82(1): 61–5
Denke MA. Combination therapy. J Manag Care Pharm 2003; 9 (1 Suppl.): 17–9
Gupta EK, Ito MK. Ezetimibe: the first in a novel class of selective cholesterol-absorption inhibitors. Heart Dis 2002; 4(6): 399–409
Zetia [package insert]. North Wales (PA): Merck/Schering-Plough Pharmaceuticals, 2005
Van Heek M, France CF, Compton DS, et al. In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461. J Pharmacol Exp Ther 1997; 283(1): 157–63
Van Heek M, Farley C, Compton DS, et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 2000; 129(8): 1748–54
Knopp RH, Gitter H, Traitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003; 24(8): 729–41
Van Heek M, Farley C, Compton DS, et al. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function. Br J Pharmacol 2001; 134(2): 409–17
Bays HE, Moore PB, Drehobl MA, et al. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther 2001; 23(8): 1209–30
Gagne C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002; 90(10): 1084–91
Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002; 105(21): 2469–75
Kerzner B, Corbelli J, Sharp S, et al. Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003; 91(4): 418–24
Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40(12): 2125–34
Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003; 107(19): 2409–15
Melani L, Mills R, Hassman D, et al. Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Eur Heart J 2003; 24(8): 717–28
Zhu Y, Statkevich P, Kosoglou T, et al. Effect of ezetimibe (SCH 58235) on the activity of drug metabolizing enzymes in vivo [abstract]. Clin Pharmacol Ther 2000; 67(2): 152
Patrick JE, Kosoglou T, Stauber KL, et al. Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. Drug Metab Dispos 2002; 30(4): 430–7
Ezzet F, Krishna G, Wexler DB, et al. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther 2001; 23(6): 871–85
Rosenblum SB, Huynh T, Afonso A, et al. Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption. J Med Chem 1998; 41(6): 973–80
Altmann SW, Davis Jr HR, Zhu LJ, et al. Niemann-Pick C1 Like 1 (NPCILI) is critical for intestinal cholesterol absorption. Science 2004; 303(5661): 1201–4
Watts G. The yin and yang of cholesterol ester transferase proteins and atherosclerosis. Clin Sci 2002; 103: 595–7
Salen G, von Bergmann K, Lutjohann D, et al. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation 2004; 109: 966–7
Zbaida S, Alton K, Shannon D, et al. In vitro metabolism of SCH 58235, 1-(4-fluorophenyl)-3R-[3-(4-fluorophenyl)-3S-hydroxypropyl]-4S-(4-hydroxyphenyl)-2-azetidinone, by liver and kidney slices. 12th International Symposium of Microsomes and Drug Oxidations; 1998 Jul 20–24; Montpellier
Data on file, Schering-Plough Corporation
Ghosal A, Hapangama N, Yuan Y, et al. Identification of human UDP-glucuronosyltransferase enzymes(s) responsible for the glucuronidation of ezetimibe. Drug Metab Dispos 2004; 32(3): 314–20
Data on file, Merck & Co., Inc.
Kosoglou T, Meyer I, Veltri EP, et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol 2002; 54(3): 309–19
Keung ACF, Kosoglou T, Statkevich P, et al. Ezetimibe does not affect the pharmacokinetics of oral contraceptives [abstract]. Clin Pharmacol Ther 2001; 69(2): P55
Statkevich P, Zhu Y, Kosoglou T, et al. SCH 58235 does not affect the pharmacokinetics of simvastatin [abstract]. Clin Pharmacol Ther 2000; 67(2): 146
Reyderman L, Kosoglou T, Statkevich P, et al. No pharmacokinetic drug interaction between ezetimibe and lovastatin [abstract]. Clin Pharmacol Ther 2001; 69(2): P66
Zhu Y, Statkevich P, Kosoglou T, et al. Lack of a pharmacokinetic interaction between ezetimibe and atorvastatin [abstract]. Clin Pharmacol Ther 2001; 69(2): P68
Reyderman L, Kosoglou T, Boutros T, et al. Pharmacokinetic interaction between ezetimibe and lovastatin in healthy volunteers. Curr Med Res Opin 2004; 20(9): 1493–500
Bauer KS, Statkevich P, Kosoglou T, et al. Ezetimibe (SCH 58235) does not affect the pharmacokinetics and pharmacodynamics of warfarin [abstract]. Clin Pharmacol Ther 2001; 69: 5
Iannucchi RM. Metabolism of SCH 58235 in the human, rat, and dog [abstract]. Proceedings of the 47th American Society of Mass Spectrometry Conference on Mass Spectrometry and Allied Topics; 1999 Jun 13–17; Dallas (TX): American Society for Mass Spectrometry, 1999: 264–5
Reyderman L, Kosoglou T, Maxwell SE, et al. Dose-proportionality of ezetimibe [abstract]. Clin Pharmacol Ther 2002; 71(2): P97
Courtney RD, Kosoglou T, Statkevich P, et al. Effect of food on the oral bioavailability of ezetimibe [abstract]. Clin Pharmacol Ther 2002; 71(2): P80
Zhu Y, Statkevich P, Kosoglou T, et al. Effect of age on the pharmacokinetics of ezetimibe [abstract]. AAPS PharmSci 2000; 2: 2082
Kosoglou T, Kakkar T, Statkevich P, et al. Multiple-dose safety and pharmacokinetics of ezetimibe in adolescent children [abstract]. Clin Pharmacol Ther 2001; 69(2): P52
Zhu Y, Statkevich P, Maxwell SE, et al. The effect of gender on the pharmacokinetics of SCH 58235, a cholesterol absorption inhibitor [abstract]. AAPS PharmSci 1999; 1 (4 Suppl. 4): S24
Reyderman L, Kosoglou T, Statkevich P, et al. Pharmacokinetics of ezetimibe in subjects with normal renal function or severe chronic renal insufficiency [abstract]. Clin Pharmacol Ther 2002; 71(2): 27
Kosoglou T, Ezzet F, Wexler D, et al. Influence of subject demographics on the pharmacokinetics of ezetimibe [abstract]. J Clin Pharmacol 2004; 44(10): 1208
Punwani N, Pai S, Bach C, et al. Effect of food on oral bioavailability of SCH 58235 in healthy male volunteers [abstract]. AAPS PharmSci 1998; 1 (1 Suppl.): S486
Stein EA. Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J 2001; 3(E Suppl.): E11–6
Melani L, Lipka L, Sager PT, et al. Efficacy and safety of ezetimibe coadministered with statins in elderly patients with hypercholesterolemia [abstract]. J Am Geriatr Soc 2003; 51 (4 Suppl.): S85
Bennett SK, Huttner RP, Lipka L, et al. Efficacy and safety of ezetimibe coadministered with statins in male and female patients [abstract]. Obstet Gynecol 2004; 109 (8 Suppl.): 966–71
Wahllander A, Beuers U. The prognostic value of liver function tests: clinical aspects, laboratory chemical parameters and quantitative function tests. Leber Magen Darm 1990; 20(3): 115–26
Reyderman L, Statkevich P, Kosoglou T, et al. No pharmacokinetic drug interaction between ezetimibe and either cerivastatin or fluvastatin [online]. AAPS Pharm Sci 2001; 3 (3 Suppl.): Available from URL: http://www.aapspharmaceutica.com/search/abstract_view.asp?id=331&ct=01 Abstracts [Accessed 2005 Mar 29]
Kosoglou T, Statkevich P, Meyer I, et al. Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin. Curr Med Res Opin 2004; 20(6): 955–65
Kosoglou T, Statkevich P, Yang B, et al. Pharmacodynamic interaction between ezetimibe and rosuvastatin. Curr Med Res Opin 2004; 20(8): 1185–95
Reyderman L, Kosoglou T, Statkevich P, et al. Assessment of a multiple-dose drug interaction between ezetimibe and gemfibrozil [abstract]. XIV International Symposium on Drugs Affecting Lipid Metabolism; 2001 Sep 9–12; New York
Reyderman L, Kosoglou T, Statkevich P, et al. Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor, and gemfibrozil. Int J Clin Pharmacol Ther 2004; 42(9): 512–8
Kosoglou T, Statkevich P, Reyderman L, et al. Effects of selected drugs on exposure to ezetimibe [abstract]. Eur Heart J 2003; 24 Suppl.: 462
Kosoglou T, Statkevich P, Fruchart JC, et al. Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe. Curr Med Res Opin 2004; 20(8): 1197–207
Reyderman L, Kosoglou T, Maxwell SE. Lack of pharmacokinetic interaction between ezetimibe and fenofibrate [online]. AAPS Pharm Sci Suppl 2001; 3 (3): Available from URL: http://www.aapspharmaceutica.com/search/abstract_view.asp?id=326&ct=01Abstracts [Accessed 2005 Mar 29]
Statkevich P, Reyderman L, Kosoglou T, et al. Ezetimibe does not affect the pharmacokinetics and pharmacodynamics of glipizide [abstract]. Clin Pharmacol Ther 2001; 69(2): P67
Courtney RD, Kosoglou T, Statkevich P, et al. Effect of antacid on the pharmacokinetics of ezetimibe [abstract]. Clin Pharmacol Ther 2002; 71(2): P80
Krishna G, Kosoglou T, Ezzet F, et al. Effect of Cimetidine on the pharmacokinetics of ezetimibe [online]. AAPS Pharm Sci Suppl 2001; 3 (3): Available from URL: http://www.aapspharmaceutica.com/search/abstract_view.asp?id=819&ct=01Abstracts [Accessed 2005 Mar 29]
Bergman A, Johnson-Levonas A, Burke J, et al. Assessment of pharmacokinetic interactions between ezetimibe and cyclosporine [abstract]. Clin Pharmacol Ther 2005; 77(2): P75
Kosoglou T, Statkevich P, Bauer KS, et al. Ezetimibe does not affect the pharmacokinetics and pharmacodynamics of digoxin [online]. AAPS Pharm Sci Suppl 2001; 3 (3): Available from URL: http://www.aapspharmaceutica.com/search/abstract_view.asp?id=290&ct=01Abstracts [Accessed 2005 Mar 29]
Kosoglou T, Seiberling M, Statkevich P, et al. Pharmacodynamic interaction between cerivastatin and the selective cholesterol absorption inhibitor ezetimibe [abstract]. Eur Heart J 2001; 22 Suppl.: 252
Kosoglou T, Meyer I, Musiol B, et al. Pharmacodynamic interaction between fluvastatin and ezetimibe has favorable clinical implications [abstract]. Atherosclerosis 2001; 2(2): 89
Kosoglou T, Seiberling M, Statkevich P, et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and atorvastatin [abstract]. J Am Coll Cardiol 2001; 37 (A Suppl.): 229A
Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002; 41(5): 343–70
McTaggart F, Buckett L, Davidson R, et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001; 87(5A): 28–32B
Jacobsen W, Kirchner G, Hallensleben K, et al. Comparison of cytochrome P450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab Dispos 1999; 27(2): 173–9
Gruer PJ, Vega JM, Mercuri MF, et al. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 1999; 84(7): 811–5
Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet 1998; 34(2): 155–62
Ast M, Frishman WH. Bile acid sequestrants. J Clin Pharmacol 1990; 30(2): 99–106
Lebovitz HE. Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev 2002; 18 (2 Suppl.): S23–9
Humphries TJ, Merritt GJ. Review article: drug interactions with agents used to treat acid-related diseases. Aliment Pharmacol Ther 1999; 13 (3 Suppl.): 18–26
Acknowledgements
The authors wish to thank Michelle Zakson-Aiken for her help in preparing this manuscript for publication.
Drs Kosoglou and Statkevich and Mr Alton are employees of Schering-Plough Corporation, Kenilworth, New Jersey, USA. Drs Johnson-Levonas, Bergman and Paolini are employees of Merck & Co., Inc., Rahway, New Jersey, and Blue Bell, Pennsylvania, USA. The funding for this paper was provided by Merck/Schering-Plough Pharmaceuticals, North Wales, Pennsylvania, USA.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kosoglou, T., Statkevich, P., Johnson-Levonas, A. et al. Ezetimibe. Clin Pharmacokinet 44, 467–494 (2005). https://doi.org/10.2165/00003088-200544050-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200544050-00002