Prasugrel

Synonyms :
Effient, Prasugrel, SID124899264

Status : approved

Category

Platelet Aggregation Inhibitors

Therapeutic Classification

ANTITHROMBOTIC AGENTS

BLOOD AND BLOOD FORMING ORGANS
ANTITHROMBOTIC AGENTS
ANTITHROMBOTIC AGENTS

Description

Prasugrel, a thienopyridine derivative, is a platelet activation and aggregation inhibitor structurally and pharmacologically related to clopidogrel and ticlopidine. Similar to clopidogrel, prasugrel is a prodrug that requires enzymatic transformation in the liver to its active metabolite, R-138727. R-138727 irreversibly binds to P2Y12 type ADP receptors on platelets thus preventing activation of the GPIIb/IIIa receptor complex. As a result, inhibition of ADP-mediated platelet activation and aggregation occurs. Prasugrel was developed by Daiichi Sankyo Co. and is currently marketed in the United States and Canada in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention (PCI). FDA approved in 2009.

Used

Indicated in combination with acetylsalicylic acid (ASA) to prevent atherothrombotic events in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI). May be used in patients with unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI) who are to be managed with PCI. Prasugrel is not recommended in patients 75 years of age or greater, those that weigh<60kg, and patients with a history of stroke or transient ischemic attack due to increased risk of fatal and intracranial bleeding.

Mechanism Of Action

Prasugrel is an thienopyridine and a prodrug which inhibits ADP receptors by irreversibly acting on the P2Y12 receptor on platelets. The active metabolite of prasugrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. Prasugrel is proposed to have a similar mechanism of action to clopidogrel.

Dosage

Form Route Strength
Tablet oral 10 mg
Tablet, film coated oral 10 mg
Tablet, film coated oral 5 mg

Pharmacodynamics

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. The increased potency of prasugrel appears to be due to more efficient conversion to its active metabolite. However, it carries a higher risk of bleed compared to clopidogrel, which may be a result of its higher potency. Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.

Toxic Effect

LD50 (rat) 1,000 – 2,000 mg/kg; LD50 (rabbit) > 1,000 mg/kg

Metabolism

Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to thiolactone by human carboxylesterase (hCE) 2. This intermediate is further metabolized to its active metabolite, R-138727, in a single step by cytochrome P450 enzymes in the liver (primarily CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19). The active metabolite is further metabolized by S-methylation or cysteine conjugation to two inactive metabolites. Unlike clopidogrel, transformation of prasugrel to its active metabolite does not appear to be affected by cytochrome P450 polymorphisms.

Absorption

79% or greater of the dose is absorbed after oral administration. Absorption and metabolism occur rapidly and peak plasma concentrations (Cmax) are reached approximately 30 minutes following oral administration. Administration with a high fat, high calorie meal did not affect the AUC of the active metabolite in healthy individuals, but the Cmax was decreased by ~49% and the Tmax was increased to 0.5 to 1.5 hours. Prasugrel may be administered with or without food.

Half Life

The active metabolite has an elimination half-life of about 7.4 hours (range 2-15 hours).

Protein Binding

Approximately 98% of the active metabolite was bound to human serum albumin in a 4% buffered solution. The major inactive metabolites are also highly bound to human plasma proteins.

Elimination Route

Approximately 68% of the orally administered dose is excreted in urine and 27% in the feces, as inactive metabolites. The active metabolite is not expected to be removed by dialysis.

Clearance

Apparent clearance = 112 – 166 L/hr

Volume of Distribution

44-68L

Chemical Classification

This compound belongs to the class of organic compounds known as phenylpropylamines. These are compounds containing a phenylpropylamine moiety, which consists of a phenyl group substituted at the third carbon by an propan-1-amine.

Phenylpropylamines

Organic compounds

Benzenoids

Benzene and substituted derivatives

Phenylpropylamines

Salt : Prasugrel Hydrochloride

Chemical Name

Effient

Brands

name Dosage form Country
Effient tablet Canada
Effient tablet, film coated US
Effient tablet, film coated US
Effient tablet, film coated US
Effient tablet, film coated US

Drug Drug Interactions

  •  Abciximab  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Acenocoumarol  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Acetylsalicylic acid  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result.
  •  Alteplase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Anistreplase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Apixaban  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased.
  •  Atazanavir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Boceprevir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Cangrelor  : May diminish the antiplatelet effect of Prasugrel. More specifically, while the use of Cangrelor is expected to increase total platelet inhibition in patients who have previously received Prasugrel, Cangrelor is expected to decrease binding of Prasugrel metabolites to P2Y12 receptors and thus reduce the extent of irreversible platelet inhibition.
  •  Ceritinib  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Citric Acid  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Clarithromycin  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Cobicistat  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Dabigatran etexilate  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran etexilate. This mechanism applies specifically to clopidogrel.
  •  Dalteparin  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Darunavir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Dasatinib  : May enhance the anticoagulant effect of Agents with Antiplatelet Properties.
  •  Deoxycholic Acid  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased.
  •  Dicoumarol  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Edetic Acid  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Enoxaparin  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Ethyl biscoumacetate  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Fondaparinux sodium  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Glucosamine  : May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
  •  Heparin  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Ibritumomab  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding.
  •  Ibrutinib  : May enhance the adverse/toxic effect of Agents with Antiplatelet Properties.
  •  Idelalisib  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Indinavir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Itraconazole  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Ketoconazole  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Lopinavir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Nefazodone  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Nelfinavir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Obinutuzumab  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.
  •  Pentosan Polysulfate  : May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents.
  •  Pentoxifylline  : May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
  •  Phenindione  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Phenprocoumon  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Posaconazole  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Ranitidine  : May decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Reteplase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Ridogrel  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Rifampicin  : May diminish the antiplatelet effect of Prasugrel.
  •  Ritonavir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Rivaroxaban  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban.
  •  Salicylate-sodium  : Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result.
  •  Saquinavir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Streptokinase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Sulodexide  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Telaprevir  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Telithromycin  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Tenecteplase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents.
  •  Tipranavir  : May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
  •  Treprostinil  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.
  •  Urokinase  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase.
  •  Vitamin E  : May enhance the antiplatelet effect of Agents with Antiplatelet Properties.
  •  Voriconazole  : CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel.
  •  Warfarin  : Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants.

Food Interactions

  • Despite being a CYP3A4 inducer, grapefruit juice does not affect the pharmacokinetics of prasugrel

Calculated Property

kind Value Source
logP 3.67 ALOGPS
logS -5.2 ALOGPS
Water Solubility 2.37e-03 g/l ALOGPS
logP 4.31 ChemAxon
IUPAC Name 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4H,5H,6H,7H-thieno[3,2-c]pyridin-2-yl acetate ChemAxon
Traditional IUPAC Name prasugrel ChemAxon
Molecular Weight 373.441 ChemAxon
Monoisotopic Weight 373.114792406 ChemAxon
SMILES CC(=O)OC1=CC2=C(CCN(C2)C(C(=O)C2CC2)C2=CC=CC=C2F)S1 ChemAxon
Molecular Formula C20H20FNO3S ChemAxon
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 ChemAxon
InChIKey InChIKey=DTGLZDAWLRGWQN-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 46.61 ChemAxon
Refractivity 96.81 ChemAxon
Polarizability 37.7 ChemAxon
Rotatable Bond Count 6 ChemAxon
H Bond Acceptor Count 3 ChemAxon
H Bond Donor Count 0 ChemAxon
pKa (strongest acidic) 14.25 ChemAxon
pKa (strongest basic) 5.48 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 4 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 1 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • P2Y purinoceptor 12 : in Human