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An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT-HF Substudy

Journal article
Authors J. A. Batty
A. S. Hall
H. L. White
John Wikstrand
R. A. de Boer
D. J. van Veldhuisen
P. van der Harst
Finn Waagstein
Åke Hjalmarson
J. Kjekshus
A. J. Balmforth
Published in Clinical Pharmacology & Therapeutics
Volume 95
Issue 3
Pages 321-330
ISSN 0009-9236
Publication year 2014
Published at Wallenberg Laboratory
Pages 321-330
Language en
Links dx.doi.org/10.1038/clpt.2013.193
Keywords RANDOMIZED INTERVENTION TRIAL, CYTOCHROME-P450 2D6, ANKYLOSING-SPONDYLITIS, CLINICAL-OUTCOMES, ADVERSE EVENTS, BETA-BLOCKERS, TASK-FORCE, PHARMACOKINETICS, METABOLISM, OXIDATION
Subject categories Clinical pharmacology

Abstract

To explore the pharmacogenetic effects of the cytochrome P450 (CYP) 2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional * 4 allele (1846G> A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6* 4 allele (EM: * 1* 1, 60.4%; IM: * 1* 4, 35.8%; and PM: * 4* 4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6* 4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.

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