Bempedoic Acid And Ezetimibe
Bempedoic Acid And Ezetimibe Uses, Dosage, Side Effects, Food Interaction and all others data.
High levels of LDL cholesterol (LDL-C) are a major risk factor for cardiovascular events. Caused by genetic mutations or lifestyle factors, hypercholesterolemia can significantly reduce quality of life and increase the risk of mortality from cardiovascular disease. About 1 in 4 patients, or 15 million Americans with elevated LDL-C, are insufficiently managed with maximally tolerated statin therapy alone, requiring additional treatment for hypercholesterolemia.
Bempedoic acid is first-in-class adenosine triphosphate-citrate lyase (ACL) inhibitor used once a day for reducing LDL cholesterol levels in statin-refractory patients. It was developed by Esperion Therapeutics Inc. and approved by the FDA on February 21, 2020. A combination product of bempedoic acid and ezetimibe was approved on February 26, 2020 for increased control of LDL cholesterol levels in patients experiencing refractory elevations despite previous statin treatment.
Bempedoic acid inhibits the synthesis of cholesterol in the liver, reducing LDL-C levels. This reduces the development of atherosclerotic plaques that may increase the risk of cardiovascular events. Earlier clinical trials studying the effects of bempedoic acid showed a dose‐dependent reduction of LDL‐C levels in addition to decreased LDL particle number, and reduced levels of apolipoprotein B, non–HDL cholesterol, and high‐sensitivity C‐reactive protein.
Ezetimibe localises at the brush border of the small intestine and inhibits absorption of cholesterol via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1). This results in decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores and increased clearance of cholesterol from the blood.
Ezetimibe was shown to reduce the levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone. In clinical trials involving patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia, a recommended therapeutic dose of ezetimibe was effective in reducing the LDL levels by 15-20% while increasing HDL-C by 2.5-5%.
The effects of increased exposure to ezetimibe secondary to moderate-severe hepatic impairment have not been assessed - patients meeting these criteria should avoid the use of ezetimibe. Post-marketing reports indicate the potential for myopathy and rhabdomyolysis in patients taking ezetimibe, and this risk appears to be exacerbated in patients concurrently receiving, or having recently received, statin therapy.
| Trade Name | Bempedoic Acid And Ezetimibe |
| Generic | bempedoic acid + ezetimibe |
| Weight | 180mg + 10mg |
| Type | Oral tablet |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Bempedoic acid is a drug used in conjunction with lifestyle modification and/or other agents for the treatment of refractory hypercholesterolemia.
Bempedoic acid is indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or existing atherosclerotic cardiovascular disease that warrants additional lowering of LDL-C.
The combination of bempedoic and ezetimibe is also indicated with diet management and maximally tolerated statin therapy to treat elevated LDL-C levels in adults with heterozygous familial hypercholesterolemia or existing atherosclerotic cardiovascular disease who require further lowering of LDL-C.
Primary Hypercholesterolemia: Ezetimibe co-administered with statin is used for adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolemia who are not appropriately controlled with a statin alone.Ezetimibe monotherapy is used for adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolemia in whom a statin is considered inappropriate or is not tolerated.
Prevention of Cardiovascular Events: Ezetimibe is used to reduce the risk of cardiovascular events in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) when added to ongoing statin therapy or initiated concomitantly with a statin.
Homozygous Familial Hypercholesterolaemia (HoFH): Ezetimibe co-administered with a statin, is used for adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g., LDL apheresis).
Homozygous Sitosterolemia (Phytosterolemia): Ezetimibe is used for adjunctive therapy to diet for use in patients with homozygous familial sitosterolemia
Bempedoic Acid And Ezetimibe is also used to associated treatment for these conditions: Atherosclerotic Cardiovascular Diseases, Heterozygous Familial HypercholesterolemiaElevated Blood Lipids, Elevated sitosterol and campesterol
How Bempedoic Acid And Ezetimibe works
Normally, LDL cholesterol is produced in the liver and circulates in the blood. When the blood becomes saturated, excess LDL deposits in blood vessels including the coronary arteries, increasing the risk of cardiovascular events.
Bempedoic acid is a prodrug that requires activation in the liver. The very-long-chain acyl-CoA synthetase-1 (ACSVL1) enzyme is responsible for its activation to ETC-1002-CoA, the pharmacologically active metabolite. ATP lyase (also known as ATP synthase) plays an important part of cholesterol synthesis. BETC-1002-CoA directly inhibits this enzyme after the parent drug is activated in the liver by coenzyme A (CoA).
This inhibition leads to upregulation of the LDL cholesterol receptor, reducing serum LDL-C via increased uptake and LDL clearance in the liver. By the above mechanisms, bempedoic acid causes a total decrease of circulating LDL-C that normally damages blood vessels and leads to atherosclerosis. Lastly, ETC-1002 activates AMP-activated protein kinase (AMPK) in rodents, which inhibits the synthesis of cholesterol via the inhibition of HMG-CoA reductase. The relevance of this to humans is unknown.
Ezetimibe mediates its blood cholesterol-lowering effect via selectively inhibiting the absorption of cholesterol and phytosterol by the small intestine without altering the absorption of fat-soluble vitamins and nutrients. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed on enterocytes/gut lumen (apical) as well as the hepatobiliary (canalicular) interface and plays a role in facilitating internalization of free cholesterol into the enterocyte in conjunction with the adaptor protein 2 (AP2) complex and clathrin. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it binds to the sterol-sensing domain of NPC1L1 and forms a NPC1L1/cholesterol complex. The complex is then internalized or endocytosed by joining to AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment.
Ezetimibe does not require exocrine pancreatic function for its pharmacological activity; rather, it localizes and appears to act at the brush border of the small intestine. Ezetimibe selectively blocks the NPC1L1 protein in the jejunal brush border, reducing the uptake of intestinal lumen micelles into the enterocyte. Overall, ezetimibe causes a decrease in the delivery of intestinal cholesterol to the liver and reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. While the full mechanism of action of ezetimibe in reducing the entry of cholesterol into both enterocytes and hepatocytes is not fully understood, one study proposed that ezetimibe prevents the NPC1L1/sterol complex from interacting with AP2 in clathrin coated vesicles and induces a conformational change in NPC1L1, rendering it incapable of binding to sterols. Another study suggested that ezetimibe disrupts the function of other protein complexes involved in regulating cholesterol uptake, including the CAV1–annexin 2 heterocomplex.
Dosage
Bempedoic Acid And Ezetimibe dosage
The recommended dose of Ezetimibe is 10 mg once daily. Ezetimibe can be administered with or without food.
Side Effects
Clinical studies of Ezetimibe (administered alone or with an HMG-CoA reductaseinhibitor) demonstrated that Ezetimibe was generally well tolerated. The overallincidence of adverse events reported with Ezetimibe was similar to that reported withplacebo, and the discontinuation rate due to adverse events was also similar for Ezetimibeand placebo.
Toxicity
LD50 information for bempedoic acid is not readily available in the literature. In the case of an overdose with bempedoic acid, contact the local poison control center. To this date, there is no experience with bempedoic acid overdoses. Employ general supportive measures.
Oral LD50 and intraperitoneal LD50 in rat were >2000 mg/kg. Estimated oral LD50 values in mouse and dog are >5000 mg/kg and >3000 mg/kg, respectively. One case of accidental overdose occurred in clinical studies in one female patient with homozygous sitosterolemia receiving 120 mg/day for 28 days with no reported clinical or laboratory adverse events. In case of overdose, symptomatic treatment is recommended.
Precaution
Exclude or treat secondary causes of dyslipidaemia prior to initiating therapy. Renal and hepatic impairment. Pregnancy and lactation.
Interaction
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in animals, Ezetimibe increased cholesterol in the gallbladder bile. Coadministration of Ezetimibe with fibrates is not therefore recommended until use in patients is studied.
Volume of Distribution
The apparent volume of distribution of bempedoic acid is about 18L.
The relative volume of distribution of ezetimibe is 107.5L.
Elimination Route
Bempedoic acid is rapidly absorbed in the small intestine. The Tmax of the 180mg tablet is estimated at 3.5 hours.
Administration of a single 10-mg dose of ezetimibe in fasted adults resulted in peak plasma concentrations (Cmax) of 3.4-5.5 ng/mL within 4-12 hours (Tmax). The Cmax of the major pharmacologically-active metabolite, ezetimibe-glucuronide, was 45-71 ng/mL and its Tmax was 1-2 hours. Food consumption has minimal effect on ezetimibe absorption, but the Cmax is increased by 38% when administered alongside a high-fat meal. The true bioavailability of ezetimibe cannot be determined, as it is insoluble in aqueous media suitable for intravenous injection.
Half Life
The half-life of bempedoic acid ranges between 15 and 24 hours. Prescribing information indicates a clearance of 21 hours +/- 11 hours.
Both ezetimibe and ezetimibe-glucuronide display an approximate half-life of 22 hours.
Clearance
The clearance (CL/F) of bempedoic acid at steady state was estimated at 11.2 mL/min during clinical trials.
There are no pharmacokinetic data available on the clearance of ezetimibe.
Elimination Route
Bempedoic acid's conjugates are primarily eliminated via the urine (70%) and the feces (30%). A total of 5% of the unchanged drug is excreted in the urine and feces, combined.
Approximately 78% and 11% of orally administered radiolabelled ezetimibe are recovered in the feces and urine, respectively. Unchanged parent drug is the major component in feces and accounts for approximately 69% of an administered dose, while ezetimibe-glucuronide is the major component in urine and accounts for approximately 9% of an administered dose. High recovery of unchanged parent drug in feces suggests low absorption and/or hydrolysis of ezetimibe-glucuronide secreted in the bile.
Pregnancy & Breastfeeding use
There are no adequate and well-controlled studies of Ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus
Contraindication
Hypersensitivity to any component of this medication. The combination of Ezetimibewith an HMG-CoA reductase inhibitor is contraindicated in patients with active liverdisease or unexplained persistent elevations in serum transaminases.
Special Warning
Pediatric Use-
10 to 17 years: No dosage adjustment is required. The clinical experience in pediatric and adolescent patients is however limited. When Ezetimibe is administered with statin, the dosage instructions for statin, in adolescents should be consulted.
Children < 10 years: Ezetimibe is not recommended for use in children below age 10 due to insufficient data on safety and efficacy.
Acute Overdose
No cases of overdosage with Ezetimibe have been reported. Administration of Ezetimibe,50 mg/day, to 15 subjects for up to 14 days was generally well tolerated. In the event ofan overdose, symptomatic and supportive measures should be employed.
Storage Condition
Store in a cool & dry place protected from light and moisture. Keep out of reach of children.
Innovators Monograph
You find simplified version here Bempedoic Acid And Ezetimibe
