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FORMATION OF THE ACTIVE METABOLITE OF
EFFIENT® (PRASUGREL)

  • Effient, a thienopyridine, is a prodrug that is rapidly metabolized to its active metabolite1

Metabolism of Effient and clopidogrel

Metabolism of Effient® & Clopidogrel

Active Metabolite*

No relevant effect of genetic variation in CYP2C19

*Effient is not 100% converted to the active metabolite, as a portion of the dose is metabolized directly to inactive metabolites.

Active Metabolite

Genetic variation in CYP2C19 can impair the metabolism of clopidogrel

hCE=human carboxylesterase
CYP=cytochrome P450

Intermediate

Intermediate

Any difference in the formation of the active metabolite of Effient compared with clopidogrel has not been correlated to clinical outcomes.

Absorption and binding of Effient

  • Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite1
  • In a study of healthy subjects given a single 15-mg dose, the AUC of the active metabolite was unaffected by a high-fat, high-calorie meal, but Cmax was decreased by 49% and Tmax was increased from 0.5 to 1.5 hours. Effient can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin1

Metabolism and elimination of Effient

  • The active metabolite has an elimination half-life of about 7 hours (range 2–15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics1
  • Effient is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C191
  • The estimates of apparent volume of distribution of the Effient active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the Effient dose is excreted in the urine and 27% in the feces as inactive metabolites1

SELECTED SAFETY: EFFIENT INCREASED THE RISK OF TIMI MAJOR OR MINOR BLEEDING VS CLOPIDOGREL

Effient can cause significant, sometimes fatal, bleeding. Overall rates of non-CABG TIMI major or minor bleeding were significantly higher with Effient plus ASA (4.5%) compared with clopidogrel plus ASA (3.4%). The rates of fatal bleeding were 0.3% with Effient plus ASA and 0.1% with clopidogrel plus ASA. In patients who underwent CABG (N=437), the rates of CABG-related TIMI major or minor bleeding were 14.1% with Effient plus ASA and 4.5% with clopidogrel plus ASA.

Next: TRITON-TIMI 38 Trial Design

References: 1. Effient® (prasugrel) prescribing information. Daiichi Sankyo, Inc. and Eli Lilly and Company. 2. Rehmel JLF, Eckstein JA, Farid NA, et al. Drug Metab Dispos. 2006;34:600-607. 3. Williams ET, Jones KO, Ponsler GD, et al. Drug Metab Dispos. 2008;36:1227-1232. 4. Farid NA, Kurihara A, Wrighton SA. J Clin Pharmacol. 2010;50:126-142. 5. Savi P, Pereillo JM, Uzabiaga MF, et al. Thromb Haemost. 2000;84:891-896. 6. Kurihara A, Hagihara K, Kazui M, Ozeki T, Farid NA, Ikeda T. Drug Metab Rev. 2005;37(suppl 2):99. 7.  Lagorce P, Perez Y, Ortiz J, Necciari J, Bressolle F. J Chromatogr B Biomed Sci Appl. 1998;720:107-117. 8. Tang M, Mukundan M, Yang J, et al. J Pharmacol Exp Ther. 2006;319:1467-1476. 9. Plavix® (clopidogrel bisulfate) prescribing information. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. 10. Kazui M, Nishiya Y, Ishizuka T, et al. Drug Metab Dispos. 2010;38:92-99.

INDICATION

Effient® (prasugrel) is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows:

  • Patients with unstable angina (UA) or non–ST-elevation myocardial infarction (NSTEMI)
  • Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI

The loading dose (LD) of Effient is 60 mg and the maintenance dose (MD) is 10 mg once daily. Effient is available in 5-mg and 10-mg tablets.

IMPORTANT SAFETY INFORMATION

WARNING: BLEEDING RISK

Effient® (prasugrel) can cause significant, sometimes fatal, bleeding.

Do not use Effient in patients with active pathological bleeding or a history of transient ischemic attack or stroke.

In patients ≥75 years of age, Effient is generally not recommended, because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior myocardial infarction [MI]) where its effect appears to be greater and its use may be considered.

Do not start Effient in patients likely to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue Effient at least 7 days prior to any surgery.

Additional risk factors for bleeding include:

  • body weight <60 kg
  • propensity to bleed
  • concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs [NSAIDs])

Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of Effient.

If possible, manage bleeding without discontinuing Effient. Discontinuing Effient, particularly in the first few weeks after acute coronary syndrome, increases the risk of subsequent cardiovascular events.

CONTRAINDICATIONS

  • Effient is contraindicated in patients with active pathological bleeding, such as from a peptic ulcer or intracranial hemorrhage (ICH), or a history of transient ischemic attack (TIA) or stroke, and in patients with hypersensitivity to prasugrel or any component of the product

WARNINGS AND PRECAUTIONS

  • Patients who experience a stroke or TIA while on Effient generally should have therapy discontinued. Effient should also be discontinued for active bleeding and elective surgery
  • Premature discontinuation of Effient increases risk of stent thrombosis, MI, and death
  • Thrombotic thrombocytopenic purpura (TTP), a rare but serious condition that can be fatal, has been reported with Effient, sometimes after a brief exposure (<2 weeks), and requires urgent treatment, including plasmapheresis
  • Hypersensitivity, including angioedema, has been reported in patients receiving Effient, including patients with a history of hypersensitivity reaction to other thienopyridines

ADVERSE REACTIONS

  • Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction

Please see Prescribing Information, including Boxed Warning regarding bleeding risk, and Medication Guide.