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Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes: An analysis of the AleCardio trial

Journal article
Authors J. V. Koomen
H. J. L. Heerspink
I. C. Schrieks
G. G. Schwartz
M. Lincoff
S. J. Nicholls
A. Svensson
Hans Wedel
A. Weichert
D. E. Grobbee
J. Stevens
Published in Diabetes Obesity & Metabolism
ISSN 1462-8902
Publication year 2019
Published at Institute of Medicine
Language en
Links dx.doi.org/10.1111/dom.13862
Keywords aleglitazar, exposure response, peroxisome proliferator-activated receptor, PK-PD, randomized, type-2 diabetes-mellitus, acute coronary syndrome, alpha/gamma agonist, clopidogrel, pharmacokinetics, metabolism, aspirin, events, Endocrinology & Metabolism
Subject categories Cardiac and Cardiovascular Systems

Abstract

Aims The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-alpha gamma agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. Materials and Methods The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 mu g or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population. Results Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma-concentration-time curve (AUC(0-24)) of 174.7 ng h/mL (SD: +/- 112.9 ng h/mL) versus 142.2 ng h/mL (SD: +/- 92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002, <0.001 and < 0.001, respectively). Conclusions Concomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar.

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