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

• Published in: Cancer chemotherapy and pharmacology Vol. 71; no. 3; pp. 565 - 573
• Main Authors: Heath, Elisabeth I., Infante, Jeffrey, Lewis, Lionel D., Luu, Thehang, Stephenson, Joe, Tan, Antoinette R., Kasubhai, Saifuddin, LoRusso, Patricia, Ma, Bo, Suttle, A. Benjamin, Kleha, Joseph F., Ball, Howard A., Dar, Mohammed M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.03.2013; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Algorithms; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - pharmacokinetics; Anti-Bacterial Agents - pharmacokinetics; Antineoplastic agents; Aza Compounds - pharmacokinetics; Biological and medical sciences; Blood Pressure - drug effects; Cancer Research; Confidence Intervals; Double-Blind Method; Electrocardiography, Ambulatory; Female; Fluoroquinolones; Heart Conduction System - drug effects; Heart Rate - drug effects; Humans; Indazoles; Long QT Syndrome - chemically induced; Long QT Syndrome - physiopathology; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Moxifloxacin; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - complications; Neoplasms - drug therapy; Neoplasms - physiopathology; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Quinolines - pharmacokinetics; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Tumors; Young Adult; QTc; Moxifloxacin; Safety; Pharmacokinetics; Tyrosine kinase inhibitor; Pazopanib; QT interval; Solid tumor; Enzyme; Toxicity; Transferases; Oral administration; Enzyme inhibitor; Cardiovascular disease; Malignant tumor; Multiple dose; Fluoroquinolone derivatives; Randomization; Placebo; Double blind study; Protein-tyrosine kinase; Quinolone derivatives; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-2030-8

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.