|Trade names||Effient, Efient|
|Protein binding||Active metabolite: ~98%|
|Elimination half-life||~7 h (range 2 h to 15 h)|
|Excretion||Urine (~68% inactive metabolites); feces (27% inactive metabolites)|
|Chemical and physical data|
|Molar mass||373.442 g/mol g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Prasugrel (trade name Effient in the US, Australia and India, and Efient in the EU) is a drug 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 currently marketed in the United States in cooperation with Eli Lilly and Company.
Prasugrel was approved for use in Europe in February 2009, 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).
Prasugrel is used in combination with low dose aspirin to prevent thrombosis in patients with ACS, including unstable angina pectoris, non-ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI), who are planned for treatment with PCI. In studies, prasugrel was more effective than the related clopidogrel but also caused more bleeding. Overall mortality was the same.
Prasugrel does not change the risk of death when given to people who have had a STEMI or NSTEMI. Prasugrel does however increase the risk of bleeding and may decrease the risk of further cardiovascular problems. Thus routine use in NSTEMI patients is of questionable value.
Prasugrel should not be given to patients 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).
Adverse effects include:
- 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
Mechanism of action
Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine (trade name Ticlid) and clopidogrel (trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors. Compared to clopidogrel, prasugrel inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI. 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. Unlike clopidogrel, prasugrel is effective in most individuals, although several cases have been reported of decreased responsiveness to prasugrel.
Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. 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.
Prasugrel is a prodrug and is rapidly metabolized by carboxylesterase 2 in the intestine and carboxylesterase 1 in the liver to a likewise inactive thiolactone, which is then converted by CYP3A4 and CYP2B6, and to a minor extent by CYP2C9 and CYP2C19, to a pharmacologically active metabolite (R-138727). R-138727 has an 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.
U.S. National Center for Biotechnology Information: Medical Genetics Summaries - Prasugrel Therapy and CYP Genotype
- US 5288726 claims prasugrel compound; expired on 14 Apr 2017
- US 6693115 claims hydrochloride salt of prasugrel; will expire on 3 Jul 2021
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