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
| Autor: | Mohammed M. Dar, Lionel D. Lewis, Howard A. Ball, Thehang Luu, Jeffrey R. Infante, Bo Ma, Elisabeth I. Heath, Antoinette R. Tan, Patricia LoRusso, Saifuddin M. Kasubhai, Joe Stephenson, Joseph F. Kleha, A. Benjamin Suttle |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Indazoles medicine.drug_class Moxifloxacin Placebo-controlled study Urology Angiogenesis Inhibitors Blood Pressure Pharmacology Toxicology Tyrosine-kinase inhibitor Article Pazopanib Young Adult Growth factor receptor Double-Blind Method Heart Conduction System Heart Rate Neoplasms Cardiac conduction medicine Confidence Intervals Humans Pharmacology (medical) Aged Cardiotoxicity Aza Compounds Sulfonamides business.industry Cancer Middle Aged medicine.disease Anti-Bacterial Agents Long QT Syndrome Pyrimidines Oncology Electrocardiography Ambulatory Quinolines Female business Tyrosine kinase Algorithms medicine.drug Fluoroquinolones |
| Zdroj: | Cancer chemotherapy and pharmacology. 71(3) |
| ISSN: | 1432-0843 |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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