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

Autor: Koomen JV; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Heerspink HJL; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Schrieks IC; Julius Clinical & Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands., Schwartz GG; Cardiology Section, Rocky Mountain Regional VA Medical Center and University of Colorado School of Medicine, Colorado, Aurora., Lincoff AM; C5Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio., Nicholls SJ; Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia., Svensson A; Clinical Development, Cardio Metabolism, F. Hoffmann-La Roche Ltd., Basel, Switzerland., Wedel H; Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Weichert A; Product Development, Immunology, Infectious Disease and Ophthalmology (I2O), F. Hoffmann-La Roche Ltd., Basel, Switzerland., Grobbee DE; Julius Clinical & Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands., Stevens J; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2020 Jan; Vol. 22 (1), pp. 30-38. Date of Electronic Publication: 2019 Oct 01.
DOI: 10.1111/dom.13862
Abstrakt: Aims: The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-αγ 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 μg 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.
(© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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