The influence of body size on the pharmacodynamic and pharmacokinetic response to clopidogrel and prasugrel: A retrospective analysis of the FEATHER study

• Published in: Thrombosis research Vol. 134; no. 3; pp. 552 - 557
• Main Authors: Jakubowski, Joseph A., Angiolillo, Dominick J., Zhou, Chunmei, Small, David S., Moser, Brian A., ten Berg, Jurrien M., Brown, Patricia B., James, Stefan, Winters, Kenneth J., Erlinge, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.09.2014
• Subjects: Adult; Aged; Biomarkers - blood; Blood Platelets - drug effects; Blood Platelets - metabolism; Body Mass Index; Body Size; Body Surface Area; Body Weight; Cardiac and Cardiovascular Systems; Cardiology and Cardiovascular Disease; Cell Adhesion Molecules - blood; Clinical Medicine; Clopidogrel; Coronary Artery Disease - blood; Coronary Artery Disease - diagnosis; Coronary Artery Disease - drug therapy; Drug Dosage Calculations; Female; Hematology, Oncology and Palliative Medicine; Humans; Kardiologi; Kardiologi och kardiovaskulära sjukdomar; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Microfilament Proteins - blood; Middle Aged; Pharmacodynamics; Pharmacokinetics; Phosphoproteins - blood; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Function Tests; Prasugrel; Prasugrel Hydrochloride - administration & dosage; Prasugrel Hydrochloride - pharmacokinetics; Purinergic P2Y Receptor Antagonists - administration & dosage; Purinergic P2Y Receptor Antagonists - pharmacokinetics; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12 - blood; Receptors, Purinergic P2Y12 - drug effects; Retrospective Studies; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacokinetics; Treatment Outcome; PRI; Clop; TRITON-TIMI 38; ADP; AUC; PRP; BSA; PPP; Body mass index; R; PRU; BW; MD; HBW; BMI; LBW; VASP; Cmax; Pharmacodynamics; PGE1; CAD; MEA; AM; Prasugrel; ACS; Pras; PD; PCI; IRB; LD; LTA; Clopidogrel; PK; Pharmacokinetics; MPA; coronary artery disease; pharmacodynamics; multiple electrode aggregometry; body weight; percutaneous coronary intervention; low body weight; vasodilator-associated stimulated phosphoprotein; maximum platelet aggregation; adenosine diphosphate; prostaglandin E 1; body mass index; loading dose; high body weight; PGE 1; area under the concentration-time curve; maximum concentration; VerifyNow-P2Y12 reaction units; clopidogrel; prasugrel; light transmission aggregometry; maintenance dose; TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis In Myocardial Infarction 38; C max; range; institutional review board; platelet reactivity index; acute coronary syndrome; active metabolite; pharmacokinetics; platelet-rich plasma; platelet-poor plasma; body surface area
• ISSN: 0049-3848; 1879-2472; 1879-2472
• DOI: 10.1016/j.thromres.2014.05.019

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 75mg (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. Aspirin-treated patients with stable coronary artery disease (N=72) and a BW range of 45-134kg 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. 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). 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.