Prasugrel

Source: Wikipedia, the free encyclopedia.
Prasugrel
Clinical data
Trade namesEffient, Efient
AHFS/Drugs.comMonograph
MedlinePlusa609027
License data
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
Bioavailability≥79%
Protein bindingActive metabolite: ~98%
Elimination half-life~7 h (range 2 h to 15 h)
ExcretionUrine (~68% inactive metabolites); feces (27% inactive metabolites)
Identifiers
  • (RS)-5-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-
    tetrahydrothieno[3,2-c]pyridin-2-yl acetate
JSmol)
  • CC(=O)Oc1cc2c(s1)CCN(C2)C(c3ccccc3F)C(=O)C4CC4
  • InChI=1S/C20H20FNO3S/c1-12(23)25-18-10-14-11-22(9-8-17(14)26-18)19(20(24)13-6-7-13)15-4-2-3-5-16(15)21/h2-5,10,13,19H,6-9,11H2,1H3 checkY
  • Key:DTGLZDAWLRGWQN-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Prasugrel, sold under the brand name Effient in the US, Australia and India, and Efient in the EU) is a medication used to prevent

Ube and marketed in the United States in cooperation with Eli Lilly and Company
.

Prasugrel was approved for use in the European Union in February 2009,[1] and in the US in July 2009, for the reduction of thrombotic cardiovascular events (including stent thrombosis) in people with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI).[2]

Medical uses

Prasugrel is used in combination with

STEMI), who are planned for treatment with PCI. Prasugrel is associated with a higher bleeding risk compared to clopidogrel but has demonstrated superiority in reducing the composite endpoint of death, recurrent myocardial infarctions and stroke.[3]

Prasugrel does not change the risk of death when given to people who have had a STEMI[citation needed] or NSTEMI.

Given the risk of bleeding, prasugrel should not be used in people who are older than 75 years, who have low body weight or a history of transient ischemic attacks or strokes.[3][4] The initiation of prasugrel before coronary angiography outside the context of primary PCI is not recommended.[5][6][4]

Approval status

The drug was introduced to clinical practice in Canada in 2010 [7] but was subsequently withdrawn by the manufacturer in 2020 as a "business decision". This has left a gap in the management of high-risk patients in certain situations in Canada where Effient was the drug of choice.[8]

Contraindications

Prasugrel should not be given to people with active pathological bleeding, such as peptic ulcer or a history of transient ischemic attack or stroke, because of higher risk of stroke (thrombotic stroke and intracranial hemorrhage).[9]

Adverse effects

Adverse effects include:[10]

  • Cardiovascular: Hypertension (8%), hypotension (4%), atrial fibrillation (3%), bradycardia (3%), noncardiac chest pain (3%), peripheral edema (3%), thrombotic thrombocytopenic purpura (TTP)
  • Central nervous system: Headache (6%), dizziness (4%), fatigue (4%), fever (3%), extremity pain (3%)
  • Dermatologic: Rash (3%)
  • Endocrine and metabolic: Hypercholesterolemia/hyperlipidemia (7%)
  • Gastrointestinal: Nausea (5%), diarrhea (2%), gastrointestinal hemorrhage (2%)
  • Hematologic: Leukopenia (3%), anemia (2%)
  • Neuromuscular and skeletal: Back pain (5%)
  • Respiratory: Epistaxis (6%), dyspnea (5%), cough (4%)
  • Hypersensitivity, including angioedema

Interactions

Prasugrel has a low potential for interactions. It may, for example, be used with

proton pump inhibitors to reduce the risk of gastrointestinal bleeding without loss of its antiplatelet effect.[11][12][13][14]

Pharmacology

Mechanism of action

Prasugrel is a member of the

platelets by irreversibly binding to P2Y12
receptors. Prasugrel inhibits platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel.

[15][16] The TRITON-TIMI 38 study compared prasugrel with clopidogrel, and showed that prasugrel reduced rates of ischaemic events, but increased bleeding risk. Overall mortality rates were similar for each drug.[17]

Clopidogrel, unlike prasugrel, was issued a

black box warning from the FDA on March 12, 2010, as the estimated 2–14% of the US population who have low levels of the CYP2C19 liver enzyme needed to activate clopidogrel may not get the full effect. Tests are available to predict if a patient would be susceptible to this problem or not.[18][19]
Unlike clopidogrel, prasugrel is effective in most individual with the exception in patients over the age of 75, weight under 60 kg, and patients with a history of stroke or TIA due to increased risk of bleeding,[20][21] although several cases have been reported of decreased responsiveness to prasugrel.[22] It has been suggested that the decreased responsiveness observed in prasugrel is likely due to its low but significant frequency of High Platelet Reactivity (HPR).[23]

Pharmacodynamics

Prasugrel produces inhibition of

platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.[24]
Following a 60-mg loading dose of the drug, about 90% of patients had at least 50% inhibition of platelet aggregation by one hour. Maximum platelet inhibition was about 80%. Mean steady-state inhibition of platelet aggregation was about 70% following three to five days of dosing at 10 mg daily after a 60-mg loading dose. Platelet aggregation gradually returns to baseline values over five to 9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75 mg and initiating prasugrel 10 mg with the next dose resulted in increased inhibition of platelet aggregation, but not greater than that typically produced by a 10-mg maintenance dose of prasugrel alone. Increasing platelet inhibition could increase bleeding risk. The relationship between inhibition of platelet aggregation and clinical activity has not been established.[10]

Pharmacokinetics

The reaction of prasugrel (top left) to its active metabolite (R-138727, top right). The two structures at the bottom represent the inactive thiolactone; they are tautomers of each other.

Prasugrel is a

elimination half-life of about 7 hours (range 2 h to 15 h). Healthy subjects, patients with stable atherosclerosis
, and patients undergoing PCI show similar pharmacokinetics.

Chemistry

Prasugrel has one

racemic form as the hydrochloride
salt, which is a white powder.

References

  1. ^ "European Public Assessment Report for Efient" (PDF). EMA. 2009.
  2. S2CID 37160513
    .
  3. ^
    PMID 17982182
    .
  4. ^
    S2CID 13014429
    .
  5. PMID 25954988
    .
  6. S2CID 205095981
    .
  7. ^ "Product information -Effient". Health Canada. 2021. Retrieved February 18, 2021.
  8. PMID 34169260
    .
  9. ^ "Effient (prasugrel hydrochloride) Prescribing Information". U.S. Food and Drug Administration (FDA). September 2011. Archived from the original on 2017-01-18. Retrieved 2019-12-16.
  10. ^ a b "Efient (prasugrel) tablets: Highlights of prescribing information" (PDF). Eli Lilly. 2011. Archived from the original (PDF) on 31 January 2012.
  11. PMID 22570398
    .
  12. PMID 30510515
    .
  13. S2CID 205956050
    .
  14. PMID 27143321
    .
  15. PMID 17174640
    .
  16. S2CID 8226182
    .
  17. PMID 17982182
    .
  18. ^ "FDA Announces New Boxed Warning on Plavix: Alerts patients, health care professionals to potential for reduced effectiveness" (Press release). U.S. Food and Drug Administration (FDA). March 12, 2010. Archived from the original on March 15, 2010. Retrieved March 13, 2010.
  19. ^ "FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug". U.S. Food and Drug Administration (FDA). March 12, 2010. Retrieved March 13, 2010.
  20. PMID 21093072
    .
  21. PMID 17982182
    .
  22. S2CID 20617890
    .
  23. PMID 31198410
    .
  24. ^ O'Riordan M. "Switching from clopidogrel to prasugrel further reduces platelet function". TheHeart.org. Retrieved 1 April 2011.
  25. S2CID 1698598
    .
  26. PMID 26718653
    .

Further reading

External links

  • "Prasugrel". Drug Information Portal. U.S. National Library of Medicine.
  • US 5288726  claims prasugrel compound; expired on 14 April 2017
  • US 6693115  claims hydrochloride salt of prasugrel; will expire on 3 July 2021
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