イコサペント酸エチル
Ethyl eicosapentaenoic acid/ja
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| Trade names | Vascepa, Vazkepa |
| Other names | Eicosapentaenoic acid ethyl ester; Ethyl eicosapentaenoate; Eicosapent; EPA ethyl ester; E-EPA, Icosapent ethyl (USAN US) |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a613024 |
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| Routes of administration | 経口 |
| Drug class | Antilipemic Agents |
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| Formula | C22H34O2 |
| Molar mass | 330.512 g·mol−1 |
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エイコサペンタエン酸エチル（E-EPA、icosapent ethyl）は、脂質異常症および高トリグリセリド血症の治療に用いられる医薬品である。150 mg/dL以上の高トリグリセリド血症の成人には、食事の変更と併用して使用される。さらに、スタチン（最大耐用量）との併用が求められることが多い。
最も一般的な副作用は、筋骨格痛、末梢性浮腫（脚や手のむくみ）、心房細動、関節痛（関節の痛み）である。その他の一般的な副作用としては、出血、便秘、痛風、発疹などがある。
オメガ3脂肪酸から作られる。エイコサペンタエン酸（EPA）を原料としている。米国食品医薬品局（FDA）は2012年、アマリン社にイコサペントエチルの承認を与え、オメガ3酸エチルエステル（商品名Lovaza、それ自体は2004年に承認）に次ぐ2番目の魚油ベースの医薬品となった。2019年12月13日、FDAはVascepaを「トリグリセリド値が上昇した人々の心血管リスクを低減する」ことに特化した初めての薬物としても承認した。これはジェネリック医薬品として販売されている。2020年には、1 万件以上の処方で、米国で最も処方されている医薬品285位であった。
医療用途
欧州連合（EU）では、イコサペントエチルはスタチン療法の補助として心血管リスクを軽減する効能である。
In the United States, icosapent ethyl is indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adults with elevated triglyceride levels (≥ 150 mg/dL) and established cardiovascular disease or diabetes and two or more additional risk factors for cardiovascular disease. It is also indicated as an adjunct to diet to reduce triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia.
Intake of large doses (2.0 to 4.0 g/day) of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides, and at those doses the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater that 500 mg/dL). It appears that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglycerides; however, DHA alone appears to raise low-density lipoprotein (the variant which drives atherosclerosis; sometimes called "bad cholesterol") and LDL-C values (most typically only a calculated estimate and not measured by labs from person's blood sample for technical and cost reasons; however, this is accurately calculated with a less common NMR lipid panel lab), whilst eicosapentaenoic acid (EPA) alone does not and instead lowers the parameters aforementioned.
Other fish-oil based drugs
There are other omega-3 fish-oil based drugs on the market that have similar uses and mechanisms of action:
- Omega-3-acid ethyl esters (brand names Omacor [renamed Lovaza in the U.S. to avoid confusion with Amicar and Omtryg]), and as of March 2016, four generic versions
- Omega-3 carboxylic acids (Epanova); the Epanova brand name was discontinued in the United States.
Dietary supplements
There are many fish oil dietary supplements on the market.> Evidence suggests that marine based omega-3 dietary supplements are able to reduce cardiovascular disease, and premature death. These effects may not carry over in other populations such as people who have diabetes. The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been fixed and tested in clinical trials, as prescription drugs have, and the prescription forms are more concentrated, requiring fewer capsules to be taken and increasing the likelihood of compliance.
Side effects
Special caution should be taken with people who have fish and shellfish allergies. In addition, as with other omega-3 fatty acids, taking ethyl eicosapentaenoic acid (E-EPA) puts people who are on anticoagulants at risk for prolonged bleeding time. The most commonly reported side effect in clinical trials has been joint pain; some people also reported pain in their mouth or throat. E-EPA has not been tested in pregnant women; it is excreted in breast milk and the effects on infants are not known.
Pharmacology
After ingestion, ethyl eicosapentaenoic acid (E-EPA) is metabolized to eicosapentaenoic acid (EPA). EPA is absorbed in the small intestine and enters circulation. Peak plasma concentration occurs about five hours after ingestion, and the half-life is about 89 hours. EPA is lipolyzed mostly in the liver.
Mechanism of action
Eicosapentaenoic acid (EPA), the active metabolite of ethyl eicosapentaenoic acid (E-EPA), like other omega-3 fatty acid based drugs, appears to reduce production of triglycerides in the liver and to enhance clearance of triglycerides from circulating very low-density lipoprotein (VLDL) particles. The way it does that is not clear, but potential mechanisms include increased breakdown of fatty acids; inhibition of diglyceride acyltransferase, which is involved in biosynthesis of triglycerides in the liver; and increased activity of lipoprotein lipase in blood.
Chemistry
Ethyl eicosapentaenoic acid (E-EPA) is an ethyl ester of eicosapentaenoic acid, which is an omega-3 fatty acid.
History
In July 2012, the US Food and Drug Administration (FDA) approved ethyl eicosapentaenoic acid (E-EPA) for severe hypertriglyceridemia as an adjunct to dietary measures; Amarin Corporation had developed the drug. Amarin Corporation challenged the FDA's authority to limit its ability to market the drug for off-label use and won its case on appeal in 2012, changing the way the FDA regulates the marketing of medication.
Ethyl eicosapentaenoic acid (E-EPA) was the second fish-oil drug to be approved, after omega-3-acid ethyl esters (GlaxoSmithKline's Lovaza, which was approved in 2004.) Initial sales were not as robust as Amarin had hoped. The labels for the two drugs were similar, but doctors prescribed Lovaza for people who had triglycerides lower than 500 mg/dL based on some clinical evidence. Amarin wanted to actively market E-EPA for that population as well which would have greatly expanded its revenue and applied to the FDA for permission to do so in 2013, which the FDA denied. In response, in May 2015 Amarin sued the FDA for infringing its First Amendment rights, and in August 2015, a judge ruled that the FDA could not "prohibit the truthful promotion of a drug for unapproved uses because doing so would violate the protection of free speech." The ruling left open the question of what the FDA would allow Amarin to say about E-EPA, and in March 2016 the FDA and Amarin agreed that Amarin would submit specific marketing material to the FDA for the FDA to review (as is usual for prescription medications). If the parties disagreed on whether the material was truthful, they would seek a judge to mediate.
In December 2019, the FDA approved the use of icosapent ethyl as an adjunctive (secondary) therapy to reduce the risk of cardiovascular events among adults with elevated triglyceride levels (a type of fat in the blood) of 150 milligrams per deciliter or higher. People must also have either established cardiovascular disease alone or diabetes along with two or more additional risk factors for cardiovascular disease.
Icosapent ethyl is the first FDA approved drug to reduce cardiovascular risk among people with elevated triglyceride levels as an add-on to maximally tolerated statin therapy.
The efficacy and safety of icosapent ethyl were established in a study with 8,179 participants who were either 45 years and older with a documented history of coronary artery, cerebrovascular, carotid artery and peripheral artery disease or 50 years and older with diabetes and additional risk factors for cardiovascular disease. Participants who received icosapent ethyl were significantly less likely to experience a cardiovascular event, such as a stroke or heart attack.
In clinical trials, icosapent ethyl was associated with an increased risk of atrial fibrillation or atrial flutter (irregular heart rhythms) requiring hospitalization. The incidence of atrial fibrillation was greater among participants with a history of atrial fibrillation or atrial flutter. Icosapent ethyl was also associated with an increased risk of bleeding events. The incidence of bleeding was higher among participants who were also taking other medications that increase the risk of bleeding, such as aspirin, clopidogrel or warfarin at the same time.
Society and culture
Legal status
On 28 January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vazkepa, intended to reduce the risk of cardiovascular events in people at high cardiovascular risk. The applicant for this medicinal product is Amarin Pharmaceuticals Ireland Limited. It was approved for medical use in the European Union in March 2021.
