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. 2017 Aug;34(8):1615-1625.
doi: 10.1007/s11095-017-2104-8. Epub 2017 Feb 8.

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure

Jasmine A Luzum  1   2 , Kevin M Sweet  3 , Philip F Binkley  4 , Tara J Schmidlen  5 , Joseph P Jarvis  5 , Michael F Christman  5 , Wolfgang Sadee  6 , Joseph P Kitzmiller  6
Affiliations

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure

Jasmine A Luzum et al. Pharm Res. 2017 Aug.

Abstract

Purpose: This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure.

Methods: Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = 33).

Results: CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02-0.75] p = 0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84-10.30] p = 0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day).

Conclusion: Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

Keywords: CYP2D6; beta-blocker dose; carvedilol; heart failure; metoprolol; pharmacogenetics.

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Figures

Figure 1
Figure 1
Numbers of CYP2D6 metabolizer phenotypes identified according to the following three definitions (detailed definitions in Table I): *4 (rs3892097 G>A) alone, and using multiple *star alleles with the Pharmacogenomics Knowledgebase (PharmGKB®) definition (22) and the Dutch Pharmacogenetics Working Group (DPWG) definition (23). EM = extensive metabolizer; IM = intermediate metabolizer; PM = poor metabolizer.
Figure 2
Figure 2
Associations of CYP2D6 metabolizer phenotype (defined by *4 [rs3892097 G>A] alone) with maintenance doses and the achievement of guideline-recommended target doses for carvedilol (left) and metoprolol (right) in n = 98 patients with systolic heart failure. Each circle represents an individual patient. Open circles are patients that were still alive at follow-up, and red circles are patients that were deceased at follow-up. Bolded p-values are statistically significant (p < 0.05). Gray area in plot indicates the range of guideline-recommended target doses (≥ 50 mg). An “X” indicates the mean maintenance dose. EM = extensive metabolizer (zero *4 alleles); IM = intermediate metabolizer (one *4 allele); OR = odds ratio; PM = poor metabolizer (two *4 alleles)
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References

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