title: PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes.
abstract: Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84-1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77-2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77-1.27) and 1.23 (0.74-2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.
authors.affiliation: Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jmega@partners.org.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mega
authors.affiliation: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Close
authors.affiliation: Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Man
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Duvvuru
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: Cabernet Pharmaceuticals, Durham, NC, USA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Sundseth
authors.affiliation: Institut de Cardiologie, INSERM U 937, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Collet
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Delaney
authors.affiliation: Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY, USA.|Pharmacology Department, INSERM UMR S 956, Université Pierre et Marie Curie-Paris 6, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Hulot
authors.affiliation: Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac Vascular and Stroke Research Institute, McMaster University, Hamilton, ON, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
authors.affiliation: Scripps Clinic and Scripps Translational Science Institute, La Jolla, CA, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Price
authors.affiliation: I. Medizinische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Sibbing
authors.affiliation: Department of Clinical Pharmacology, AP-HP, Hôpital Saint Antoine, INSERM U-698, Paris, France.
authors.forename: Tabassome
authors.initials: T
authors.lastname: Simon
authors.affiliation: Klinik für Kardiologie und Angiologie II, Universitaets-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Trenk
authors.affiliation: Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
authors.affiliation: Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. msabatine@partners.org.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
mesh_terms: D054058:Acute Coronary Syndrome / Q000378:metabolism / Q000628:therapy; D000368:Aged; D019943:Amino Acid Substitution; D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D062645:Percutaneous Coronary Intervention; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics; D016032:Randomized Controlled Trials as Topic; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000077144:Clopidogrel; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
keywords: Clopidogrel; Genetics; PON1; Prasugrel