Prasugrel
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Clinical data | |
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Trade names | Effient, Efient |
AHFS/Drugs.com | Monograph |
MedlinePlus | a609027 |
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Routes of administration | By mouth |
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Pharmacokineticdata | |
Bioavailability | ≥79% |
Protein binding | Active metabolite: ~98% |
Eliminationhalf-life | ~7 h (range 2 h to 15 h) |
Excretion | Urine (~68% inactive metabolites); feces (27% inactive metabolites) |
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ECHA InfoCard | 100.228.719 |
Chemical and physical data | |
Formula | C20H20FNO3S |
Molar mass | 373.44g·mol−1 |
3D model (JSmol) | |
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Prasugrel,sold under the brand nameEffientin the US, Australia and India, andEfientin the EU) is a medication used to preventformation of blood clots.It is aplatelet inhibitorand an irreversible antagonist of P2Y12ADP receptors and is of thethienopyridinedrug class. It was developed byDaiichi Sankyo Co.and produced byUbeand marketed in the United States in cooperation withEli 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 (includingstentthrombosis) in people withacute coronary syndrome(ACS) who are to be managed withpercutaneous coronary intervention(PCI).[2]
Medical uses
[edit]Prasugrel is used in combination withlow dose aspirinto prevent thrombosis in patients with acute coronary syndrome, includingunstable angina pectoris,non-ST elevationmyocardial infarction(NSTEMI), and ST elevation myocardial infarction (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
[edit]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
[edit]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
[edit]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, includingangioedema
Interactions
[edit]Prasugrel has a low potential for interactions. It may, for example, be used withproton pump inhibitorsto reduce the risk of gastrointestinal bleeding without loss of its antiplatelet effect.[11][12][13][14]
Pharmacology
[edit]Mechanism of action
[edit]Prasugrel is a member of thethienopyridineclass ofADP receptorinhibitors, liketiclopidine(trade name Ticlid) andclopidogrel(trade name Plavix). These agents reduce the aggregation ( "clumping" ) ofplateletsby irreversibly binding toP2Y12receptors. 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.[3]
Clopidogrel, unlike prasugrel, was issued ablack box warningfrom the FDA on March 12, 2010, as the estimated 2–14% of the US population who have low levels of theCYP2C19liver 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.[17][18] 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,[19][3]although several cases have been reported of decreased responsiveness to prasugrel.[20]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).[21]
Pharmacodynamics
[edit]Prasugrel produces inhibition ofplatelet aggregationto 20 μM or 5 μM ADP, as measured by light transmission aggregometry.[22]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
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/3/3d/Prasugrel_activation.svg/330px-Prasugrel_activation.svg.png)
Prasugrel is aprodrugand is rapidly metabolized bycarboxylesterase 2in the intestine andcarboxylesterase 1in the liver to a likewise inactivethiolactone,which is then converted by CYP3A4 and CYP2B6, and to a minor extent by CYP2C9 and CYP2C19, to a pharmacologicallyactive metabolite(R-138727).[23][24]R-138727 has anelimination half-lifeof about 7 hours (range 2 h to 15 h). Healthy subjects, patients with stableatherosclerosis,and patients undergoing PCI show similar pharmacokinetics.
Chemistry
[edit]Prasugrel has onechiralatom. It is used inracemicform as thehydrochloridesalt, which is a white powder.
References
[edit]- ^"European Public Assessment Report for Efient"(PDF).EMA. 2009.
- ^Baker WL, White CM (2009). "Role of prasugrel, a novel P2Y(12) receptor antagonist, in the management of acute coronary syndromes".American Journal of Cardiovascular Drugs.9(4): 213–229.doi:10.2165/1131209-000000000-00000.PMID19655817.S2CID37160513.
- ^abcdWiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. (November 2007)."Prasugrel versus clopidogrel in patients with acute coronary syndromes".The New England Journal of Medicine.357(20): 2001–2015.doi:10.1056/NEJMoa0706482.PMID17982182.
- ^abChew DP, Scott IA, Cullen L, French JK, Briffa TG, Tideman PA, et al. (August 2016). "National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of acute coronary syndromes 2016".The Medical Journal of Australia.205(3): 128–133.doi:10.5694/mja16.00368.PMID27465769.S2CID13014429.
- ^Bellemain-Appaix A, Kerneis M, O'Connor SA, Silvain J, Cucherat M, Beygui F, et al. (October 2014)."Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis".BMJ.349(aug06 2): g6269.doi:10.1136/bmj.g6269.PMC4208629.PMID25954988.
- ^Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al. (September 2013)."Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes".The New England Journal of Medicine.369(11): 999–1010.doi:10.1056/NEJMoa1308075.PMID23991622.S2CID205095981.
- ^"Product information -Effient".Health Canada.2021.RetrievedFebruary 18,2021.
- ^Lordkipanidzé M, Marquis-Gravel G, Tanguay JF, Mehta SR, So DY (June 2021)."Implications of the Antiplatelet Therapy Gap Left With Discontinuation of Prasugrel in Canada".CJC Open.3(6): 814–821.doi:10.1016/j.cjco.2020.11.021.PMC8209390.PMID34169260.
- ^"Effient (prasugrel hydrochloride) Prescribing Information".U.S.Food and Drug Administration(FDA). September 2011. Archived fromthe originalon 2017-01-18.Retrieved2019-12-16.
- ^ab"Efient (prasugrel) tablets: Highlights of prescribing information"(PDF).Eli Lilly. 2011. Archived fromthe original(PDF)on 31 January 2012.
- ^John J, Koshy SK (2012)."Current oral antiplatelets: focus update on prasugrel".Journal of the American Board of Family Medicine.25(3): 343–349.doi:10.3122/jabfm.2012.03.100270.PMID22570398.
- ^Demcsák A, Lantos T, Bálint ER, Hartmann P, Vincze Á, Bajor J, et al. (2018-11-19)."PPIs Are Not Responsible for Elevating Cardiovascular Risk in Patients on Clopidogrel-A Systematic Review and Meta-Analysis".Frontiers in Physiology.9:1550.doi:10.3389/fphys.2018.01550.PMC6252380.PMID30510515.
- ^O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, et al. (September 2009). "Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials".Lancet.374(9694): 989–997.doi:10.1016/S0140-6736(09)61525-7.PMID19726078.S2CID205956050.
- ^Vaduganathan M, Cannon CP, Cryer BL, Liu Y, Hsieh WH, Doros G, et al. (September 2016)."Efficacy and Safety of Proton-Pump Inhibitors in High-Risk Cardiovascular Subsets of the COGENT Trial".The American Journal of Medicine.129(9): 1002–1005.doi:10.1016/j.amjmed.2016.03.042.PMID27143321.
- ^Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, et al. (January 2007). "A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation".American Heart Journal.153(1): 66.e9–66.16.doi:10.1016/j.ahj.2006.10.010.PMID17174640.
- ^Wiviott SD, Trenk D, Frelinger AL, O'Donoghue M, Neumann FJ, Michelson AD, et al. (December 2007). "Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial".Circulation.116(25): 2923–2932.doi:10.1161/CIRCULATIONAHA.107.740324.PMID18056526.S2CID8226182.
- ^"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 fromthe originalon March 15, 2010.RetrievedMarch 13,2010.
- ^"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.RetrievedMarch 13,2010.
- ^Ruff CT, Giugliano RP, Antman EM, Murphy SA, Lotan C, Heuer H, et al. (March 2012). "Safety and efficacy of prasugrel compared with clopidogrel in different regions of the world".International Journal of Cardiology.155(3): 424–429.doi:10.1016/j.ijcard.2010.10.040.PMID21093072.
- ^Silvano M, Zambon CF, De Rosa G, Plebani M, Pengo V, Napodano M, Padrini R (February 2011). "A case of resistance to clopidogrel and prasugrel after percutaneous coronary angioplasty".Journal of Thrombosis and Thrombolysis.31(2): 233–234.doi:10.1007/s11239-010-0533-x.PMID21088983.S2CID20617890.
- ^Warlo EM, Arnesen H, Seljeflot I (December 2019)."A brief review on resistance to P2Y12receptor antagonism in coronary artery disease ".Thrombosis Journal.17(1): 11.doi:10.1186/s12959-019-0197-5.PMC6558673.PMID31198410.
- ^O'Riordan M."Switching from clopidogrel to prasugrel further reduces platelet function".TheHeart.org.Retrieved1 April2011.
- ^Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, et al. (April 2006). "Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450".Drug Metabolism and Disposition.34(4): 600–607.doi:10.1124/dmd.105.007989.PMID16415119.S2CID1698598.
- ^Kurokawa T, Fukami T, Yoshida T, Nakajima M (March 2016)."Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog".Drug Metabolism and Disposition.44(3): 409–416.doi:10.1124/dmd.115.068221.PMID26718653.
Further reading
[edit]- Dean L (2017)."Prasugrel Therapy and CYP Genotype".In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.).Medical Genetics Summaries.National Center for Biotechnology Information(NCBI).PMID28520385.Bookshelf ID: NBK425796.
External links
[edit]- "Prasugrel".Drug Information Portal.U.S. National Library of Medicine.
- US 5288726claims prasugrel compound; expired on 14 April 2017
- US 6693115claims hydrochloride salt of prasugrel; will expire on 3 July 2021