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


CONCLUSIONS
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.
Center for Pharmacogenomics, Ohio State University College of Medicine, Columbus, Ohio, USA. jluzum@umich.edu.|Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church St., Ann Arbor, Michigan, 48109, USA. jluzum@umich.edu.
Jasmine A
JA
Luzum
Division of Human Genetics, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, Ohio, USA.
Kevin M
KM
Sweet
Division of Cardiovascular Medicine and the Dorothy M. Davis Heart and Lung Research Institute, Ohio State University College of Medicine, Columbus, Ohio, USA.
Philip F
PF
Binkley
Coriell Institute for Medical Research, Camden, New Jersey, USA.
Tara J
TJ
Schmidlen
Coriell Institute for Medical Research, Camden, New Jersey, USA.
Joseph P
JP
Jarvis
Coriell Institute for Medical Research, Camden, New Jersey, USA.
Michael F
MF
Christman
Center for Pharmacogenomics, Ohio State University College of Medicine, Columbus, Ohio, USA.
Wolfgang
W
Sadee
Center for Pharmacogenomics, Ohio State University College of Medicine, Columbus, Ohio, USA.
Joseph P
JP
Kitzmiller
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002227:Carbazoles / Q000008:administration & dosage; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000008:administration & dosage; D012189:Retrospective Studies
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol
CYP2D6; beta-blocker dose; carvedilol; heart failure; metoprolol; pharmacogenetics