Vorapaxar

Last updated
Vorapaxar
Vorapaxar structure.svg
Vorapaxar ball-and-stick model.png
Clinical data
Trade names Zontivity
Other namesSCH-530348
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~100% [2]
Protein binding ≥99%
Metabolism hepatic (CYP3A4 and CYP2J2)
Elimination half-life 5–13 days
Excretion feces (58%), urine (25%)
Identifiers
  • Ethyl N-[(3R,3aS,4S,4aR,7R,8aR,9aR)-4-[(E)-2-[5-(3-fluorophenyl)-2-pyridyl]vinyl]-3-methyl-1-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3H-benzo[f]isobenzofuran-7-yl]carbamate
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.116.767 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C29H33FN2O4
Molar mass 492.591 g·mol−1
3D model (JSmol)
Melting point 278 °C (532 °F)
  • Fc1cccc(c1)c2ccc(nc2)\C=C\[C@H]4[C@H]3[C@@H](C[C@H](NC(=O)OCC)CC3)C[C@H]5C(=O)O[C@@H]([C@@H]45)C
  • InChI=1S/C29H33FN2O4/c1-3-35-29(34)32-23-10-11-24-20(14-23)15-26-27(17(2)36-28(26)33)25(24)12-9-22-8-7-19(16-31-22)18-5-4-6-21(30)13-18/h4-9,12-13,16-17,20,23-27H,3,10-11,14-15H2,1-2H3,(H,32,34)/b12-9+/t17-,20+,23-,24-,25+,26-,27+/m1/s1 X mark.svgN
  • Key:ZBGXUVOIWDMMJE-QHNZEKIYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Vorapaxar (brand name Zontivity, formerly known as SCH 530348) is a thrombin receptor (protease-activated receptor, PAR-1) antagonist based on the natural product himbacine, discovered by Schering-Plough and developed by Merck & Co. [3]

Contents

Medical uses

Vorapaxar is used for persons with a history of myocardial infarction (heart attack) or persons with peripheral arterial disease. Studies have shown that this medication can reduce the rate of combined endpoint cardiovascular death, MI, stroke, and urgent coronary revascularization. [2]

Contraindications

Vorapaxar is contraindicated for people with a history of stroke, transient ischemic attack, or intracerebral hemorrhage. [2] In studies of vorapaxar on persons with prior ischemic stroke, there was an increased risk of intracranial hemorrhage without an improvement in major vascular events. Vorapaxar possesses a long half-life, which is problematic because there is currently no treatment to reverse the antiplatelet effects of vorapaxar. [2] This family of medication, PAR-1 antagonists in general, has been associated with an increased risk of intracranial bleeding, as demonstrated by a pooled analysis of data that studied 42,000 patients with history of thrombotic vascular disease or acute coronary syndrome comparing the medication and a placebo. [4]

Drug interactions

Vorapaxar is eliminated primarily via metabolism by the CYP3A enzymes. It is best to avoid strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, and conivaptan. CYP3A4 inducers, such as carbamazepine, rifampin, St. John's wort, and phenytoin, should also be avoided. [2]

Dose adjustment

No dose adjustment is required in persons with renal impairment. [2] No dose adjustment is required in persons with mild and moderate hepatic impairment. If the person has severe hepatic impairment, vorapaxar is not recommended due to the risk of bleeding. [2]

Mechanism of action

Vorapaxar is an antiplatelet drug of the PAR-1 antagonist family. It functions by inhibiting thrombin-related platelet aggregation. This mechanism works by a different pathway from other antiplatelet medications, such as aspirin and P2Y12 inhibitors. Vorapaxar does not affect ADP-mediated platelet aggregation, coagulation parameters, or bleeding time. [5]

Storage

Vorapaxar can be stored at 20–25 °C (68–77 °F). It is best to store vorapaxar in original packaging with the bottle tightly closed and to avoid moisture. [2]

History

In January 2011, clinical trials being conducted by Merck were halted for patients with stroke and mild heart conditions due to an increase in brain bleeding. [6] In a randomized double-blind trial comparing vorapaxar with placebo in addition to standard therapy in patients who had acute coronary syndromes, there was no significant reduction in a composite end point of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. However, there was increased risk of major bleeding. [7] A trial published in February 2012 found no change in all-cause mortality while decreasing the risk of cardiac death and increasing the risk of major bleeding, including intracranial hemorrhages. After two years, the data and safety monitoring board recommended discontinuation of the study treatment in people with a history of stroke owing to the risk of intracranial hemorrhage.

The TRA 2°P–TIMI 50 study of vorapaxar was carried out in patients who had previously experienced a heart attack, stroke, or who had peripheral arterial disease (PAD). In this three-year study, the addition of vorapaxar to standard of care (aspirin and/or an ADP antagonist such as clopidogrel) significantly reduced the risk of the primary composite endpoint of cardiovascular death, heart attack, stroke, or urgent coronary revascularization by 12 percent compared to placebo plus standard of care. Vorapaxar showed the most promising results among patients with a history of heart attack. Among these patients, the drug reduced the relative risk of cardiovascular death, heart attack, or stroke by 20 percent. There was an increase in moderate or severe bleeding, but no statistically significant increase in fatal bleeding. [8] Vorapaxar was recommended for FDA approval on January 15, 2014, [9] and obtained it on May 5, 2014.

Related Research Articles

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Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever.

<span class="mw-page-title-main">Coronary artery disease</span> Reduction of blood flow to the heart

Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the cardiac muscle due to build-up of atherosclerotic plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. Types include stable angina, unstable angina, and myocardial infarction.

<span class="mw-page-title-main">Angina</span> Chest discomfort from heart muscles

Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.

An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation where classical Vitamin K antagonist anticoagulants have minimal effect.

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.

<span class="mw-page-title-main">Cerebrovascular disease</span> Condition that affects the arteries that supply the brain

Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The most common presentation of cerebrovascular disease is an ischemic stroke or mini-stroke and sometimes a hemorrhagic stroke. Hypertension is the most important contributing risk factor for stroke and cerebrovascular diseases as it can change the structure of blood vessels and result in atherosclerosis. Atherosclerosis narrows blood vessels in the brain, resulting in decreased cerebral perfusion. Other risk factors that contribute to stroke include smoking and diabetes. Narrowed cerebral arteries can lead to ischemic stroke, but continually elevated blood pressure can also cause tearing of vessels, leading to a hemorrhagic stroke.

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<span class="mw-page-title-main">Clopidogrel</span> Antiplatelet medication

Clopidogrel, sold under the brand name Plavix among others, is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following the placement of a coronary artery stent. It is taken by mouth. Its effect starts about two hours after intake and lasts for five days.

<span class="mw-page-title-main">Abciximab</span>

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<span class="mw-page-title-main">Prasugrel</span> Medication used to prevent formation of blood clots

Prasugrel, sold under the brand name Effient in the US, Australia and India, and Efient in the EU) is a medication used to prevent formation of blood clots. It is a platelet inhibitor and an irreversible antagonist of P2Y12 ADP receptors and is of the thienopyridine drug class. It was developed by Daiichi Sankyo Co. and produced by Ube and marketed in the United States in cooperation with Eli Lilly and Company.

<span class="mw-page-title-main">Hypertensive emergency</span> Very high blood pressure and signs of organ damage

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Intracerebral hemorrhage (ICH), also known as hemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. An ICH is a type of bleeding within the skull and one kind of stroke. Symptoms can vary dramatically depending on the severity, acuity, and location (anatomically) but can include headache, one-sided weakness, numbness, tingling, or paralysis, speech problems, vision or hearing problems, memory loss, attention problems, coordination problems, balance problems, dizziness or lightheadedness or vertigo, nausea/vomiting, seizures, decreased level of consciousness or total loss of consciousness, neck stiffness, and fever.

<span class="mw-page-title-main">Tirofiban</span> Antiplatelet drug

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<span class="mw-page-title-main">Bivalirudin</span> Anticoagulant drug

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Himbacine is an alkaloid isolated from the bark of Australian magnolias. Himbacine has been synthesized using a Diels-Alder reaction as a key step. Himbacine's activity as a muscarinic receptor antagonist, with specificity for the muscarinic acetylcholine receptor M2, made it a promising starting point in Alzheimer's disease research. The development of a muscarinic antagonist based on himbacine failed but an analog, vorapaxar, has been approved by the FDA as a thrombin receptor antagonist.

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<span class="mw-page-title-main">Darexaban</span> Chemical compound

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References

  1. "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada . 14 March 2017. Retrieved 7 April 2024.
  2. 1 2 3 4 5 6 7 8 "ZONTIVITY™ (vorapaxar) Tablets 2.08 mg, for oral use. Full Prescribing Information" (PDF). Merck & Co., Inc. Initial U.S. Approval: 05/2014. Retrieved 17 June 2014.
  3. Chackalamannil S, Wang Y, Greenlee WJ, Hu Z, Xia Y, Ahn HS, et al. (June 2008). "Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity". Journal of Medicinal Chemistry. 51 (11): 3061–3064. doi:10.1021/jm800180e. PMID   18447380.
  4. Morrow DA, Alberts MJ, Mohr JP, Ameriso SF, Bonaca MP, Goto S, et al. (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–TIMI 50 Steering Committee and Investigators) (March 2013). "Efficacy and safety of vorapaxar in patients with prior ischemic stroke". Stroke. 44 (3): 691–698. doi: 10.1161/STROKEAHA.111.000433 . PMID   23396280. S2CID   25848104.
  5. Baker NC, Lipinski MJ, Lhermusier T, Waksman R (October 2014). "Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting about vorapaxar". Circulation. 130 (15): 1287–1294. doi:10.1161/circulationaha.114.011471. PMID   25287768. S2CID   26737510.
  6. Cortez MF, Randall T (13 January 2011). "Merck Blood Thinner Studies Halted in Select Patients". Bloomberg News .
  7. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, et al. (January 2012). "Thrombin-receptor antagonist vorapaxar in acute coronary syndromes". The New England Journal of Medicine. 366 (1): 20–33. doi:10.1056/NEJMoa1109719. hdl: 2445/49763 . PMID   22077816.
  8. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, et al. (April 2012). "Vorapaxar in the secondary prevention of atherothrombotic events". The New England Journal of Medicine. 366 (15): 1404–1413. doi:10.1056/NEJMoa1200933. hdl: 10447/94482 . PMID   22443427. S2CID   205094316.
  9. "Merck Statement on FDA Advisory Committee for Vorapaxar, Merck's Investigational Antiplatelet Medicine". Merck. 15 January 2014. Archived from the original on 20 January 2014. Retrieved 16 January 2014.

Further reading