Pharmacokinetics
Effient® (prasugrel) is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites.1
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 pharmacokinetics.1
Formation of Active Metabolite
Any difference in the formation of the active metabolite of Effient compared with Plavix® (clopidogrel bisulfate) has not been correlated to clinical outcomes.
Absorption and binding
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 metabolite.1
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 the time to reach Cmax (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 albumin.1
Metabolism and elimination
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 CYP2C19.1
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 metabolites.1
SELECTED SAFETY: BLEEDING RATES IN TRITON-TIMI 38
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 Plavix plus ASA (3.4%). The rates of fatal bleeding were 0.3% with Effient plus ASA and 0.1% with Plavix 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 Plavix plus ASA. Click here for Safety Information and Boxed Warning.
References:
- Effient® (prasugrel) prescribing information. Daiichi Sankyo, Inc. and Eli Lilly and Company.
- Rehmel JLF, Eckstein JA, Farid NA, et al. Drug Metab Dispos. 2006;34:600-607.
- Williams ET, Jones KO, Ponsler GD, et al. Drug Metab Dispos. 2008;36:1227-1232.
- Farid NA, Kurihara A, Wrighton SA. J Clin Pharmacol. 2010;50:126-142.
- Savi P, Pereillo JM, Uzabiaga MF, et al. Thromb Haemost. 2000;84:891-896.
- Kurihara A, Hagihara K, Kazui M, Ozeki T, Farid NA, Ikeda T. Drug Metab Rev. 2005;37(S2):99.
- Lagorce P, Perez Y, Ortiz J, Necciari J, Bressolle F. J Chromatogr B Biomed Sci Appl. 1998;720:107-117.
- Tang M, Mukundan M, Yang J, et al. J Pharmacol Exp Ther. 2006;319:1467-1476.
- Plavix® (clopidogrel bisulfate) prescribing information. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.