Ezetimibe
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Ezetimibe
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| Systematic (IUPAC) name | |
| (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one | |
| Identifiers | |
| CAS number | |
| ATC code | C10 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | C24H21F2NO3 |
| Mol. mass | 409.4 g.mol-1 |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | 35–65% |
| Protein binding | >90% |
| Metabolism | Intestinal wall, hepatic |
| Half life | 19–30 hours |
| Excretion | Renal 11%, faecal 78% |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
S4 (Au), POM (UK), ℞-only (U.S.) |
| Routes | Oral |
Ezetimibe (pronounced /ɛˈzɛtəmɪb/) is an anti-hyperlipidemic medication that is used to lower cholesterol levels. It acts by decreasing cholesterol absorption in the intestine. It may be used alone when other cholesterol-lowering medications are not tolerated, or together with statins (e.g. ezetimibe/simvastatin, marketed as Vytorin and Inegy) when cholesterol levels are unable to be controlled on statins alone. Ezetimibe was originally discovered by a team of four Schering-Plough research chemists: Drs. Stuart B. Rosenblum, Duane A. Burnett, John W. Clader and Brian A. McKittrick.
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[edit] Pharmacology
Ezetimibe localises at the brush border of the small intestine, where it inhibits the absorption of cholesterol from the intestine. Specifically, it appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract epithelial cells[1] as well as in hepatocytes[2]. In addition to this direct effect, decreased cholesterol absorption leads to an upregulation of LDL-receptors on the surface of cells and an increased LDL-cholesterol uptake into cells, thus decreasing levels of LDL in the blood plasma which contribute to atherosclerosis and cardiovascular events[3].
[edit] Clinical use
[edit] Indications
Ezetimibe is indicated as an adjunct to dietary measures in the management of:
- Hypercholesterolaemia
- Homozygous sitosterolemia (phytosterolemia)[4]
On 9 June 2006, U.S. regulators approved the use of ezetimibe in combination with fenofibrate to treat mixed hyperlipidaemia.
[edit] Adverse effects
Common adverse drug reactions (≥1% of patients) associated with ezetimibe therapy include: headache and/or diarrhea (steathorrea). Infrequent adverse effects (0.1–1% of patients) include: myalgia and/or raised liver function test (ALT/AST) results. Rarely (<0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur.[4]
[edit] Dosage forms
Ezetimibe is available as 10 mg tablets in most markets. A combination preparation ezetimibe/simvastatin, which combines ezetimibe with a statin, is also available.
[edit] Side effects
Side-effects include gastro-intestinal disturbances; headache, fatigue; myalgia; rarely arthralgia, hypersensitivity reactions (including rash, angioedema, and anaphylaxis), hepatitis; very rarely pancreatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis [5]
[edit] Pharmacokinetics
Ezetimibe is available as 10mg tablets. The recommended dose of ezetimibe is 10mg once daily without regard to meals for all its approved indications. Within 4-12 hours of the oral administration of a 10mg dose to fasting adults, the attained mean ezetimibe peak plasma concentration (Cmax) was 3.4—5.5 ng/ml.5 Following oral administration, ezetimibe is absorbed and extensively conjugated to a phenolic glucuronide (active metabolite). Mean Cmax (45—71 ng/ml) of ezetimibe-glucuronide are attained within 1—2 hours.5 The concomitant administration of food (high-fat vs. non-fat meals)sighas no effect on the extent of absorption of ezetimibe. However, co-administration with a highfat meal increases the Cmax of ezetimibe by 38%.5 The absolute bioavailability cannot be determined since ezetimibe is insoluble in aqueous media suitable for injection. Ezetimibe and its active metabolite are highly bound to human plasma proteins (90%).5 Ezetimibe is primarily metabolized in the liver and the small intestine via glucuronide conjugation with subsequent renal and biliary excretion. Both the parent compound and its active metabolite are eliminated from plasma with a half-life of approximately 22 hours allowing for once daily dosing. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes which explains its limited number of drug interactions (Table 4). No dose adjustment is needed in patients with renal insufficiency or mild hepatic dysfunction (Child-Pugh score 5-6). Due to insufficient data, the manufacturer does not recommend ezetimibe for patients with moderate to severe hepatic impairment (Child-Pugh score 7-15). In patients withmild, moderate, or severe hepatic impairment, the mean AUC values for total ezetimibe are increased approximately 1.7-fold, 3-4 fold, and 5-6 fold respectively, compared to healthy subjects
[edit] Clinical trial controversy
On January 14, 2008, it was reported in the New York Times that a clinical trial (ENHANCE trial) of Zetia that was designed to show that the drug could reduce the growth of fatty plaques in arteries instead resulted in growth of plaques. However, the growth noted was less than it would have been had the patients been on placebo alone. Merck and Schering-Plough completed the clinical trial in April 2006 and had initially planned to release the findings no later than March 2007. The companies missed several self-imposed deadlines, and in December 2007, finally agreed to publish the results "soon" after the delays were publicized in news reports.[6]
It should be recognized that the ENHANCE trial was not a clinical-outcome trial, but merely an imaging study. Formally, the American College of Cardiology (ACC) maintains that Zetia may be a reasonable option for patients who cannot tolerate a statin or cannot be controlled on a high dose statin. [7] The primary outcome in the treatment of hypercholesterolemia is prevention of cardiovascular events. While the ENHANCE trial did not have the power to detect significant differences in mortality, it measured the difference in carotid and femoral intima-media thickness to detect reductions in atherosclerotic plaque. At the end of two years, there was found to be no significant difference in intima-media thickness between patients taking ezetimibe and simvastatin versus patients only taking simvastatin.[8]
There has been great debate in the medical community on the use of ezetimibe in hypercholesterolemia since the publication of this trial. Despite the reduction in LDL, if ezetimibe is unable to reduce mortality, the use of the medication is futile. The ENHANCE trial moved from examining one surrogate marker to another and raised professionals to question whether reductions in LDL levels always indicate reductions in atherosclerosis. In reveiws of the ENHANCE trial, there have been questions as to whether or not the ENHANCE trial left enough time for ezetimibe to make significant reductions in atherosclerosis. Additionally, many of the patients chosen for the trial had already received lipid lowering therapy and were starting with lower baseline intima-media thickness levels than would be seen in patients naive to LDL lowering therapy, which would result in smaller decreases in intima-media thickness over the course of the trial and may have skewed the significance of the results.[9]
Results from the trial have provoked three large clinical-outcome trials. The results from these trials will be presented in the next three to four years. However, a March 30th, 2008 meeting of the ACC resulted in negative press for drugs like Zetia as Yale University Cardiologist Harlan Krumholz and concurring colleagues called into question the efficacy of such drugs. [10] Krumholz' statements maintained that such pharmaceuticals should not be the first or even second option for prescribing doctors. Definitive conclusions of the efficacy and safety of Zetia can be made such a time when the results of more substantial and comprehensive trials are released, such as the upcoming IMPROVE-IT Trial which has an enrollment of 18000 patients and will report results in 2012.
Results of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677 [ClinicalTrials.gov] ) showed a potential increase in cancer in association with the use of these drugs together. (www.nejm.org September 2, 2008 (10.1056/NEJMe0807200). The actual significance has yet to be determined.
[edit] References
- ^ Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci U S A 2005;102(23):8132-7. PMID 15928087
- ^ Temel, Ryan E., Tang, Weiqing, Ma, Yinyan, Rudel, Lawrence L., Willingham, Mark C., Ioannou, Yiannis A., Davies, Joanna P., Nilsson, Lisa-Mari, Yu, Liqing. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe J. Clin. Invest. 2007 0: JCI30060
- ^ DiPiro JT, Talbert RL, Yee GC, Marzke GR, Wells BG, Posey LM, editors. Pharmacotherapy:a pathophysiologic approach. 7th ed. New York: The McGraw-Hill Companies, Inc.; 2008.
- ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
- ^ http://www.bnf.org/bnf/bnf/current/128035.htm?q="ezetimibe"#_hit
- ^ Berenson, A (2008-01-14). "Drug Has No Benefit in Trial, Makers Say". NY Times. http://www.nytimes.com/2008/01/14/business/14cnd-drug.html?em&ex=1200459600&en=fe4f047fcd65a68e&ei=5070. Retrieved on 2008-01-14.
- ^ "ACC Statement on ENHANCE Trial". ACC. 2008-01-15. http://acc.org/enhance.htm. Retrieved on 2008-02-04.
- ^ Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, Stalenhoef AFH, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. The New England Journal of Medicine: 2008; 358(14) 1431-1443.
- ^ Brown BG, Taylor AJ. Does ENHANCE diminish confidence in lowering LDL or in ezetimibe? New England Journal of Medicine: 2005; 358: 1504-1547.
- ^ Carey, J (2008-03-31). "A Weak Prognosis for Vytorin and Zetia". Business Week. http://www.businessweek.com/bwdaily/dnflash/content/mar2008/db20080331_704360.htm?. Retrieved on 2008-04-01.
[edit] See also
[edit] External links
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