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

• Published in: Circulation (New York, N.Y.) Vol. 119; no. 19; pp. 2553 - 2560
• Main Authors: Mega, Jessica L., Close, Sandra L., Wiviott, Stephen D., Shen, Lei, Hockett, Richard D., Brandt, John T., Walker, Joseph R., Antman, Elliott M., Macias, William L., Braunwald, Eugene, Sabatine, Marc S.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 19.05.2009
• Subjects: Adult; Aged; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Biotransformation - genetics; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular Diseases - drug therapy; Cardiovascular Diseases - mortality; Cardiovascular Diseases - prevention & control; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; General and cellular metabolism. Vitamins; Genotype; Humans; Male; Medical sciences; Microsomes, Liver - enzymology; Middle Aged; Myocardial Infarction - mortality; Myocardial Infarction - prevention & control; Pharmacology. Drug treatments; Piperazines - pharmacokinetics; Piperazines - pharmacology; Piperazines - therapeutic use; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Polymorphism, Genetic; Prasugrel Hydrochloride; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Prodrugs - therapeutic use; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Stroke - mortality; Stroke - prevention & control; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; Thiophenes - therapeutic use; Treatment Outcome; Young Adult; Prasugrel; Prognosis; genetics; Enzyme; drugs; Cytochrome P450; Antithrombotic agent; Cardiovascular disease; cardiovascular diseases; Pharmacokinetics; Antiplatelet agent; Polymorphism
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.851949

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.