Published Online
on May 4, 2009

A more recent version of this article appeared on May 19, 2009

This Article Full Text (PDF) CME: Take the course for this article: Circulation: May 19, 2009, Volume 119, Number 19 Data Supplement All Versions of this Article: 119/19/2553    most recent CIRCULATIONAHA.109.851949v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mega, J. L. Articles by Sabatine, M. S. Search for Related Content PubMed PubMed Citation Articles by Mega, J. L. Articles by Sabatine, M. S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Blood Thinners Hazardous Substances DB THIOPHENE Related Collections Clinical genetics Cardiovascular Pharmacology Platelet function inhibitors Acute coronary syndromes

Submitted on January 16, 2009
Accepted on March 12, 2009

Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel. Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes

Jessica L. Mega MD, MPH^*, Sandra L. Close PhD, Stephen D. Wiviott MD, Lei Shen PhD, Richard D. Hockett MD, John T. Brandt MD, Joseph R. Walker PharmD, Elliott M. Antman MD, William L. Macias MD, PhD, Eugene Braunwald MD, and Marc S. Sabatine MD, MPH

From the Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women';s Hospital and Harvard Medical School, Boston, Mass (J.L.M., S.D.W., E.M.A., E.B., M.S.S.); Eli Lilly and Company, Indianapolis, Ind (S.L.C., L.S., J.T.B., W.L.M.); Affymetrix, Santa Clara, Calif (R.D.H.); and Daiichi Sankyo, Inc. Parsippany, NJ (J.R.W.).

^* To whom correspondence should be addressed. E-mail: jmega{at}partners.org.

Background—Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown.

Methods and Results—The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke.

Conclusions—Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications.

Key words: cardiovascular diseases • drugs • genetics

This article has been cited by other articles:

				D. P. Faxon Women are like men ... Sometimes. J. Am. Coll. Cardiol., November 17, 2009; 54(21): 1946 - 1948. [Full Text] [PDF]

				R. P. Giugliano and E. Braunwald The Year in Non-ST-Segment Elevation Acute Coronary Syndrome. J. Am. Coll. Cardiol., October 13, 2009; 54(16): 1544 - 1555. [Full Text] [PDF]

				A. Schomig Ticagrelor -- Is There Need for a New Player in the Antiplatelet-Therapy Field? N. Engl. J. Med., September 10, 2009; 361(11): 1108 - 1111. [Full Text] [PDF]

				D. L. Bhatt Tailoring Antiplatelet Therapy Based on Pharmacogenomics: How Well Do the Data Fit? JAMA, August 26, 2009; 302(8): 896 - 897. [Full Text] [PDF]

				C. Verstuyft, T. Simon, and R. B. Kim Personalized medicine and antiplatelet therapy: ready for prime time? Eur. Heart J., August 2, 2009; 30(16): 1943 - 1963. [Full Text] [PDF]

				C. S. Ernest II, M. A. Heathman, and R. E. Wrishko Prediction of Prasugrel Active Metabolite Concentrations From 2 Downstream Inactive Metabolite Concentrations Using Multilinear Regression Analysis J. Clin. Pharmacol., August 1, 2009; 49(8): 973 - 983. [Abstract] [Full Text] [PDF]

				E. Braunwald Adventures in Cardiovascular Research Circulation, July 14, 2009; 120(2): 170 - 180. [Abstract] [Full Text] [PDF]

				Antiplatelet Agent Interactions: New Data Journal Watch (General), June 11, 2009; 2009(611): 5 - 5. [Full Text]