Abstract
Purpose
As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer.
Methods
This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2–8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms.
Results
Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90 % confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90 % CI: −2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval.
Conclusions
Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.
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Acknowledgments
We thank the patients who made this study possible. We also wish to acknowledge the Study Investigators: Lee Rosen, MD, Marilyn Mulay, NP, and Jonathan Goldman, MD (Premiere Oncology, Santa Monica, CA) and Lorrin Yee, MD (Northwest Medical Specialties, Tacoma, WA); and the Study Coordinators: Nancy Gelfand (Premiere Oncology, Santa Monica, CA), Lisa Johnson, RN (Institute of Translational Oncology Research, Greenville, SC), Karen Forman, CCRP (Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI), Julie Skarsvog, RN (Northwest Medical Specialties, Tacoma, WA), Viktoria McMahan (Sarah Cannon Cancer Center, Nashville, TN), Ian Williams (The Norris Cotton Cancer Center and The Geisel School of Medicine at Dartmouth, Lebanon, NH), Abigail Guinto (City of Hope Comprehensive Cancer Center, Duarte, CA), and Shari Adams (The Cancer Institute of New Jersey, New Brunswick, NJ). This study was supported by GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania. Medical editorial assistance was provided by Jerome F Sah, PhD, at ProEd Communications, Inc., Beachwood, Ohio, and was supported by GlaxoSmithKline.
Conflict of interest
T. Luu has received research support from NCI/CTEP, Bayer/Onyx, Wyeth, Merck, Bristol-Myers Squibb, GlaxoSmithKline, and Pfizer, and has been a consultant/advisor to Novartis and Genomic Health. A. Tan has received research funding from GlaxoSmithKline. Authors Kleha, Ma, Suttle, Ball, and Dar are employees of GlaxoSmithKline. All other authors report no potential conflict of interest.
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Heath, E.I., Infante, J., Lewis, L.D. et al. A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors. Cancer Chemother Pharmacol 71, 565–573 (2013). https://doi.org/10.1007/s00280-012-2030-8
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DOI: https://doi.org/10.1007/s00280-012-2030-8