title: The influence of body size on the pharmacodynamic and pharmacokinetic response to clopidogrel and prasugrel: a retrospective analysis of the FEATHER study.
abstract: BACKGROUND
  Patients treated with clopidogrel who have higher body size exhibit greater platelet reactivity than patients with lower body size. In a retrospective analysis of the FEATHER trial, we examined the relationship between platelet response to thienopyridines clopidogrel 75 mg (Clop-75), prasugrel 5mg (Pras-5), and prasugrel 10mg (Pras-10) using 3 body size indices: body weight (BW), body mass index (BMI), and body surface area (BSA). Relationships were assessed as continuous variables and as 4 incremental body size groups.
  
  
  METHODS
  Aspirin-treated patients with stable coronary artery disease (N=72) and a BW range of 45-134 kg received Clop-75, Pras-5, and Pras-10 in a 3-period, blinded, cross-over study. Platelet assays included maximum platelet aggregation (MPA) to 20μM ADP by light transmission aggregometry, VerifyNow-P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). Exposure to active metabolites (AMs) was also assessed.
  
  
  RESULTS
  Body size was a determinant of AM exposure and residual platelet reactivity regardless of type and dose of thienopyridine. BW and BSA demonstrated marginally stronger correlations with platelet reactivity; VASP-PRI demonstrated a stronger correlation with the body size than the other tests. Correlation coefficients ranged from a high of 0.64 (BW vs. PRI on Pras-5) to a low of 0.34 (BMI vs. MPA on Pras-10), but all were statistically significant (p<0.01).
  
  
  CONCLUSIONS
  Using a comprehensive selection of body size indices, AM exposures, platelet function tests, and thienopyridine doses, we demonstrated a consistent inverse relationship between body size and response to clopidogrel and prasugrel.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: joseph@lilly.com.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.affiliation: Cardiovascular Research Center at University of Florida College of Medicine Jacksonville, FL, USA.
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Small
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Moser
authors.affiliation: St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Jurrien M
authors.initials: JM
authors.lastname: Ten Berg
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Brown
authors.affiliation: Uppsala Clinical Research Center, Uppsala, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: James
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.affiliation: Lund University, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015992:Body Mass Index; D049628:Body Size; D001830:Body Surface Area; D001835:Body Weight; D015815:Cell Adhesion Molecules / Q000097:blood; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D010750:Phosphoproteins / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D012189:Retrospective Studies; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine
keywords: Body mass index; Clopidogrel; Pharmacodynamics; Pharmacokinetics; Prasugrel