title: Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator-stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry.
abstract: ESSENTIALS: The reliability of platelet tests as markers of the variable bioavailability of clopidogrel is not yet defined. Kinetics of clopidogrel active metabolite (CAM) and platelet response were studied in ischemic heart disease. CAM plasma maximum concentration (Cmax ) predicted vasodilator-stimulated phosphoprotein (VASP-P). Timely performed VASP-P, not an aggregation-based test, may be a surrogate for clopidogrel bioavailability.
  
  
  BACKGROUND
  The high inter-individual variability in the inhibition of platelet function by clopidogrel is mostly explained by high variability in its transformation to an active metabolite (CAM). Objective We investigated the relations between pharmacokinetics and pharmacodynamics of CAM by comparing two methods of platelet function.
  
  
  METHODS
  We enrolled 14 patients undergoing percutaneous coronary interventions for non-ST-segment elevation acute coronary syndrome or inducible myocardial ischemia. Plasma concentrations of clopidogrel and CAM, phosphorylation of vasodilator-stimulated phosphoprotein (VASP-P), expressed as a platelet reactivity index (PRI) and whole-blood platelet aggregation (multiple electrode aggregometer, MEA) were measured before and after a 600-mg clopidogrel loading dose (nine time-points) and before and after 75-mg maintenance doses on days 2, 7 and 30.
  
  
  RESULTS
  Plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax ) (median, 110.8 nm; range, 41.9-484.8) 0.5-2 h after the loading dose. A sigmoid dose-response curve defined the relations between CAMCmax and PRI after 3 to 24 h (IC50 , 459.6 nm; 95% confidence interval, 453.4-465.7; R(2) = 0.82). PRI was unchanged from baseline in patients with the lowest CAMCmax (< 83 nm, n = 7), indicating low sensitivity of VASP-P. PRI values were also predicted by CAMCmax at days 2, 7 and 30. Platelet aggregation measured by MEA did not show significant relations with either PRI or with CAM pharmacokinetics at any time-point.
  
  
  CONCLUSIONS
  After 600 mg clopidogrel, VASP-P, but not whole-blood platelet aggregation measured by MEA, is almost entirely predicted by CAMCmax . VASP-P could be useful in studies aimed at investigating relations between CAM bioavailability and clinical events.
authors.affiliation: Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.|Section of Internal Medicine, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Danese
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Fava
authors.affiliation: Division of Cardiology, AOUI Verona, Verona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Beltrame
authors.affiliation: Division of Cardiology, AOUI Verona, Verona, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Tavella
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Calabria
authors.affiliation: Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Benati
authors.affiliation: Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gelati
authors.affiliation: Unit of Forensic Medicine, Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gottardo
authors.affiliation: Unit of Forensic Medicine, Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Tagliaro
authors.affiliation: Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: G C
authors.initials: GC
authors.lastname: Guidi
authors.affiliation: Unità di Medicina 3, Ospedale San Paolo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cattaneo
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, Verona, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Minuz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D054058:Acute Coronary Syndrome / Q000097:blood / Q000175:diagnosis / Q000628:therapy*; D000328:Adult; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000097:blood*; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects; D010641:Phenotype; D010750:Phosphoproteins / Q000097:blood*; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: VASP; clopidogrel; impedance aggregometry; percutaneous coronary intervention; pharmacodynamics; pharmacokinetics