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| Clinical data | |
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| Trade names | Nexletol, Nilemdo |
| Other names | ESP-55016, ETC-1002 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a620020 |
| License data | |
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| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
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| Pharmacokinetic data | |
| Protein binding | 99.3%[2] |
| Metabolism | Glucuronidation |
| Eliminationhalf-life | 21±11 hrs |
| Excretion | 70% urine, 30% feces |
| Identifiers | |
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| CAS Number | |
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| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.238.679 |
| Chemical and physical data | |
| Formula | C19H36O5 |
| Molar mass | 344.492 g·mol−1 |
| 3D model (JSmol) | |
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Bempedoic acid, sold under the brand nameNexletol among others, is a medication for the treatment ofhypercholesterolemia (high bloodcholesterol levels).[2][3]
The most common side effects includehyperuricemia (high blood levels of uric acid), pain in arms or legs, andanemia (low red blood cell counts).[3]
Bempedoic acid blocks an enzyme in the liver calledadenosine triphosphate-citrate lyase, which is involved in making cholesterol.[3]
Bempedoic acid was approved for use in the United States in February 2020, and for use in the European Union in April 2020.[3][5][6] The U.S.Food and Drug Administration (FDA) considers it to be afirst-in-class medication.[7]
In the US, bempedoic acid is indicated for the treatment of hypercholesterolemia in combination with diet and the highest toleratedstatin therapy in adults withheterozygousfamilial hypercholesterolemia, or with establishedatheroscleroticcardiovascular disease, who need additional lowering ofLDL cholesterol.[2]
In the EU, bempedoic acid is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non familial) or mixed dyslipidaemia, as an adjunct to diet in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin; or alone or in combination with other lipid-lowering therapies in patients who are statin intolerant,[8] or for whom a statin is contraindicated.[3]
Common adverse effects in clinical trials weremuscle spasms (3.6% of treated patients, as compared to 2.3% underplacebo), pain in the back (3.3% versus 2.2%) or in alimb (3.0% versus 1.7%),gout (1.5% versus 0.4%), andgastrointestinal problems such as diarrhea. A less common but more serious adverse effect wastendon rupture in therotator cuff of the shoulder, thebiceps tendon or theAchilles tendon (0.5% versus 0.0%).[2]
Bempedoic acid does not interact with thecytochrome P450 enzyme system in the liver and only weakly inhibits the transporter proteinsSLCO1B1,SLCO1B3 andSLC22A7 (the latter possibly being responsible for the increase ofuric acid in the blood, and therefore the adverse effect gout). Despite this, the drug increases blood levels of statins. The effect is most pronounced withsimvastatin andpravastatin, whoseAUC is increased about twofold. No other clinically relevant interactions have been found in studies.[2]
Bempedoic acid is aprodrug. It is activated to thethioester withcoenzyme A by the enzymeSLC27A2 in the liver.[9] The activated substance inhibitsATP citrate lyase, which is involved in the liver's biosynthesis of cholesterol upstream ofHMG-CoA reductase, the enzyme that is blocked bystatins.[10][11]
The substance also activatesAMP-activated protein kinase, but this effect is likely not relevant in humans.[9]
Following oral intake, bempedoic acid reaches highest blood plasma concentrations after 3.5 hours.[2] Food does not affect its absorption.[2] When in the bloodstream, 99.3% of the substance are bound toplasma proteins.[2] About a fifth of the substance is reversibly converted by analdo-keto reductase enzyme to ametabolite (called ESP15228) that is also pharmacologically active in form of its coenzyme A–thioester.[2] Of ESP15228, 99.2% are bound to plasma proteins.[2] Both bempedoic acid and the metabolite are inactivated byglucuronidation of theircarboxylic acid groups.[2]
Bempedoic acid has abiological half-life of 21±11 hours.[2] Over 95% of the substance are excreted in form of metabolites; about 70% with the urine and 30% with the feces.[2]
There were two clinical trials that evaluated the benefits and side effects of bempedoic acid.[6] The trial designs were similar.[6] All enrolled subjects were on a lipid-lowering diet and taking the highest dose of a statin (drug commonly used to lower cholesterol) for high cholesterol.[6] In both trials, subjects were randomly assigned to receive bempedoic acid or placebo tablets every day for 52-weeks.[6] Neither the subjects nor the health care providers knew which treatment was being given.[6] The trials measured percent change inLDL cholesterol (LDL-C) blood levels from baseline to week twelve and compared bempedoic acid to placebo.[6] In one clinical trial, bempedoic acid reduced LDL-C by about 20 mg/dl compared toplacebo and had a similar frequency of side effects to placebo, although a higher percentage of drug-receiving subjects dropped out of the study because of side effects (11% vs. 7% under placebo).[10] In onerandomized controlled trial, patients who could not tolerate therapy with statins had a reduced risk of major adverse cardiovascular events after being treated with bempedoic acid.[12]
In January 2020, theCommittee for Medicinal Products for Human Use (CHMP) in the European Union recommended granting of a marketing authorization for bempedoic acid as both a standalone drug (brand name Nilemdo)[13] and as afixed-dose combination medication withezetimibe (brand name Nustendi).[14] Bempedoic acid was approved for use in the European Union in April 2020,[3] and the combinationbempedoic acid/ezetimibe was approved in March 2020.[15][16]
In February 2020, bempedoic acid was approved for use in the United States both as a standalone drug (brand name Nexletol)[5][17][18][19] and in a fixed-dose combination with ezetimibe (brand name Nexlizet).[20] The U.S.Food and Drug Administration (FDA) granted the approval of Nexletol toEsperion Therapeutics.[2][5]
The FDA approved bempedoic acid based on evidence from two clinical trials (Trial 1/ NCT02666664 and Trial 2/NCT02991118) of 3009 subjects with high LDL cholesterol and known atherosclerotic cardiovascular disease or HeFH.[6] The trials were conducted in United States, Canada, and Europe.[6]
This article incorporates text from this source, which is in thepublic domain.