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

J. A. Batty*, A. S. Hall, H. L. White, J. Wikstrand, R. A. de Boer, D. J. van Veldhuisen, P. van der Harst, F. Waagstein, A. Hjalmarson, J. Kjekshus, A. J. Balmforth, MERIT-HF Study Grp

*Bijbehorende auteur voor dit werk

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22 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)321-330
Aantal pagina's10
TijdschriftClinical Pharmacology & Therapeutics
Volume95
Nummer van het tijdschrift3
DOI's
StatusPublished - mrt-2014

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