Vorapaxar

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Vorapaxar
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~100%[2]
Protein binding≥99%
Metabolismhepatic (CYP3A4 and CYP2J2)
Elimination half-life5–13 days
Excretionfeces (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
JSmol)
Melting point278 °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 ☒N
  • Key:ZBGXUVOIWDMMJE-QHNZEKIYSA-N ☒N
 ☒NcheckY (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]

Medical uses

Vorapaxar is used for persons with a history of

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

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

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.

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.

References

  1. ^ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada. 14 March 2017. Retrieved 7 April 2024.
  2. ^ a b c d e f g h "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. PMID 18447380
    .
  4. S2CID 25848104
    .
  5. S2CID 26737510
    .
  6. ^ Cortez MF, Randall T (13 January 2011). "Merck Blood Thinner Studies Halted in Select Patients". Bloomberg News.
  7. PMID 22077816
    .
  8. 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
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