Prasugrel

Prasugrel

Clinical data
Trade names	Effient, Efient
AHFS/Drugs.com	Monograph
MedlinePlus	a609027
License data	EU EMA: Efient US FDA: Prasugrel
Pregnancy category	US: B (No risk in non-human studies) B
Routes of administration	Oral
ATC code	B01AC22 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	≥79%
Protein binding	Active metabolite: ~98%
Biological half-life	~7 h (range 2 h to 15 h)
Excretion	Urine (~68% inactive metabolites); feces (27% inactive metabolites)
Identifiers
IUPAC name (RS)-5-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate
CAS Number	150322-43-3 N 389574-19-0 (hydrochloride)
PubChem (CID)	6918456
IUPHAR/BPS	7562
DrugBank	DB06209 Y
ChemSpider	5293653 Y
UNII	34K66TBT99 Y
KEGG	D05597 Y
ChEBI	CHEBI:87715 N
ChEMBL	CHEMBL1201772 N
ECHA InfoCard	100.228.719
Chemical and physical data
Formula	C20H20FNO3S
Molar mass	373.442 g/mol
3D model (Jmol)	Interactive image
SMILES CC(=O)Oc1cc2c(s1)CCN(C2)C(c3ccccc3F)C(=O)C4CC4
InChI 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 Y Key:DTGLZDAWLRGWQN-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Prasugrel (trade name Effient in the US and India, and Efient in the EU) is a pharmaceutical drug that acts as a platelet inhibitor and is used to prevent thrombosis (blood clotting). 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,^[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 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.^[1][3]

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.^[4]

Contraindications

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).^[5]

Adverse effects

Adverse effects include:^[6]

• 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

As opposed to clopidogrel, proton pump inhibitors do not reduce the antiplatelet effects of prasugrel and hence it is relatively safe to use these medications together.^[7]

Pharmacology

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.^[8] 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.^[9][10] Unlike clopidogrel, prasugrel is effective in most individuals, although several cases have been reported of decreased responsiveness to prasugrel.^[11]

Pharmacodynamics

Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.^[12] 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.^[6]

Pharmacokinetics

The reaction of prasugrel (top left) to its active metabolite (R-138727, top right). Unlike the related drug clopidogrel, prasugrel activation does not involve oxidation by the enzyme CYP2C19, as the relevant oxygen (at the thiophene ring) is already present in the prodrug. Instead, both the first and last steps are hydrolyses. The two structures at the bottom represent the inactive thiolactone; they are tautomers of each other.

Prasugrel is a prodrug and is rapidly metabolized by esterases in the intestine and blood serum to a likewise inactive thiolactone, which is then converted, via CYP450-mediated (primarily CYP3A4 and CYP2B6) oxidation, 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.

Chemistry

Prasugrel has one chiral atom. It is used in racemic form as the hydrochloride salt, which is a white powder.

Patents

• US 5288726  claims prasugrel compound; will expire on 14 Apr 2017
• US 6693115  claims hydrochloride salt of prasugrel; will expire on 3 Jul 2021

References