title: Higher body weight patients on clopidogrel maintenance therapy have lower active metabolite concentrations, lower levels of platelet inhibition, and higher rates of poor responders than low body weight patients.
abstract: Body weight is a predictor of clopidogrel response. However, no prospective studies have compared pharmacodynamic (PD) and pharmacokinetic (PK) data based on body weight. We compared PD and PK effects of clopidogrel 75 mg in low body weight (LBW, <60 kg) and higher body weight (HBW, ≥60 kg) patients with stable coronary artery disease. LBW (n = 34, 56.4 ± 3.7 kg) and HBW (n = 38, 84.7 ± 14.9 kg) aspirin-treated patients received clopidogrel 75 mg for 10-14 days. The area under the concentration-time curve of active metabolite (Clop-AM) calculated through the last quantifiable concentration up to 4 h postdose, AUC(0-tlast), was calculated by noncompartmental methods. Light transmission aggregometry (LTA) (maximum platelet aggregation and inhibition of platelet aggregation to 20 μM adenosine diphosphate (ADP), and residual platelet aggregation to 5 μM ADP), VerifyNow(®) P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein phosphorylation platelet reactivity index (VASP-PRI) were performed. Mean AUC(0-tlast) was lower in HBW than LBW patients: 12.8 versus 17.9 ng h/mL. HBW patients had higher platelet reactivity as measured by LTA (all p ≤ 0.01), PRU (207 ± 68 vs. 152 ± 57, p < 0.001), and VASP-PRI (56 ± 18 vs. 39 ± 17, p < 0.001). More HBW patients exhibited high on-treatment platelet reactivity (HPR) using PRU (35 vs. 9%) and VASP-PRI (65 vs. 27%). Body weight correlated with PRU and VASP-PRI (both p < 0.001), and inversely with log transformed AUC(0-tlast) (p < 0.001). In conclusion, HBW patients had lower levels of Clop-AM, and higher platelet reactivity and rates of HPR than LBW subjects, contributing to their suboptimal response to clopidogrel.
authors.affiliation: Department of Cardiology, Skane University Hospital, Lund University, Getingevägen 4, 221 85, Lund, Sweden, Henrik.wagner@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Wagner
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Jurrien M
authors.initials: JM
authors.lastname: Ten Berg
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Bergmeijer
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: David S
authors.initials: DS
authors.lastname: Small
authors.forename: Brian A
authors.initials: BA
authors.lastname: Moser
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhou
authors.forename: Patricia
authors.initials: P
authors.lastname: Brown
authors.forename: Stefan
authors.initials: S
authors.lastname: James
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000378:metabolism; D001835:Body Weight; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine
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