Role of CYP2D6 Phenotypes in Doxorubicin-Related Cardiotoxicity

Presenting Author: Oksana O. Karpenko, PharmD, RPh, BCPS, Pharmacist, Mayo Clinic, Rochester, MN

Co-Authors: Jodi L. Taraba, PharmD, MS, RPh, BCOP, Assistant Professor of Pharmacy, Mayo Clinic, Rochester, MN; Ross A. Dierkhising, MS, Principal Biostatistician, Kristin C. Cole, MS, Principal Biostatistician, Corina J. Doleski, PharmD, RPh, BCOP, Overnight Hospital Pharmacist, Mayo Clinic, Rochester, MN, Karthik V. Giridhar, MD, Medical Oncology Consultant, Mayo Clinic, Rochester, MN; Jana Kay E. Lacanlale, PharmD, RPh, PGY-1 Ambulatory Care Pharmacy Resident, William S. Middleton Memorial Veterans Hospital, Madison, WI; Jenna R. Puttkammer, PharmD, RPh, Hematology/Oncology Clinical Pharmacist, Essentia Health, Duluth, MN; Mitchell H. Wong, PharmD, RPh, PGY-1 Pharmacy Resident, UW Medicine, Seattle, WA; Jessica A. Wright, PharmD, BCACP, RPh, Assistant Professor of Pharmacy, Pharmacogenomics Pharmacist, Mayo Clinic, Rochester, MN

BACKGROUND: Cardiotoxicity is a major adverse event of doxorubicin.¹ Doxorubicin is metabolized by CYP2D6 to doxorubicinol,² which is more cardiotoxic than doxorubicin.^3,4

OBJECTIVE: To determine if increased CYP2D6 function will have an impact on the composite rate of cardiotoxicity or cardiomyopathy in patients who received doxorubicin.

METHODS: All patients who received intravenous conventional or liposomal doxorubicin between January 1, 2009, and December 31, 2021; were aged >18 years at the time of first doxorubicin administration; and had CYP2D6 genetic testing were included in our cohort. Patients were excluded from the study if they had a liver transplant before the administration of doxorubicin. Cardiomyopathy was defined as receiving a diagnosis in the medical record after the last doxorubicin dose or cardiomyopathy that occurred before doxorubicin was started but worsened after doxorubicin was completed. Worsening cardiomyopathy was defined as the reduction in left ventricular ejection fraction (LVEF) by ≥5%5 or a QTc increase of ≥30 msec from baseline after doxorubicin treatment.⁶ Cardiotoxicity was defined as a decrease of LVEF by ≥10% to a value ≤50% or a decrease in LVEF by ≥20% and/or a QTc >500 msec after the treatment or an increase in QTc by ≥60 msec from baseline.⁷ Increased CYP2D6 function included CYP2D6 ultrarapid or rapid metabolizers. CYP2D6 function that was not increased was defined as poor, intermediate, or normal metabolizers. Liposomal doxorubicin cumulative doses were converted to conventional doses. Cumulative dosing was categorized into ≤250 mg/m² or >250 mg/m².⁷ Logistic regression models were used to measure the association between CYP2D6 function and cardiotoxicity.

RESULTS: A total of 238 patients met the study inclusion criteria. Of these patients, 8 (3.4%) had CYP2D6 increased function and 230 did not have CYP2D6 increased function. A total of 43 (18.1%) patients received a cumulative doxorubicin dose of >250 mg/m². There were 36 (15.1%) patients with cardiotoxicity and/or cardiomyopathy. in all, 3 (37.5%) patients among those with a CYP2D6 increased function had cardiotoxicity or cardiomyopathy, whereas 33 (14.3%) patients among those without a CYP2D6 increased function had cardiotoxicity or cardiomyopathy (unadjusted odds ratio [OR], 3.6; 95% confidence interval [CI], 0.7-15.3; P=.091). Adjusting for the cumulative doxorubicin dose, CYP2D6 function was not significantly associated with cardiotoxicity or cardiomyopathy (adjusted OR, 3.9; 95% CI, 0.8-17.1; P=.074).

CONCLUSION: This is the first study to analyze cardiotoxicity rates based on CYP2D6 function for patients who received doxorubicin. There were numerically increased rates of cardiotoxicity or cardiomyopathy in patients with increased CYP2D6 function; however, they were not statistically significant. This study was likely underpowered because of its small sample size.

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