An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT‐HF Substudy. Issue 3 (30th September 2013)

• Record Type: Journal Article
• Authors: Batty, J A; Hall, A S; White, H L; Wikstrand, J; de Boer, R A; van Veldhuisen, D J; van der Harst, P; Waagstein, F; Hjalmarson, Å; Kjekshus, J; Balmforth, A J
• Is Part Of: Clinical pharmacology & therapeutics. Volume 95:Issue 3(2014)
• Page Start: 321
• Page End: 330
• Publication Date: 2013-09-30
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1038/clpt.2013.193
• Languages: English
• ISSNs: 0009-9236

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>*4</italic> allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT‐HF; <italic>n</italic> = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the <italic>CYP2D6*4</italic> allele (EM: <italic>*1*1</italic>, 60.4%; IM: <italic>*1*4</italic>, 35.8%; and PM: <italic>*4*4</italic>, 3.8%). Plasma metoprolol concentrations were 2.1‐/4.6‐fold greater in the IM/PM groups as compared with the EM group (<italic>P</italic> < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a <italic>CYP2D6*4</italic> allele dose–response effect (<italic>P</italic> < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. <italic>CYP2D6</italic> genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT‐HF‐defined titration schedule remains recommended for all patients, regardless of genotype.</p> <p> <italic>Clinical Pharmacology & Therapeutics</italic> (2014); <bold>95</bold> 3, 321–330. doi:<ext-link ext-link-type="doi" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">10.1038/clpt.2013.193</ext-link></p> </abstract>