Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib

• Published in: Clinical cancer research 2009-11, Vol.15 (22), p.7045-7052
• Main Authors: Bello, Carlo L, Mulay, Marilyn, Huang, Xin, Patyna, Shem, Dinolfo, Melissa, Levine, Steven, Van Vugt, Andrew, Toh, Melvin, Baum, Charles, Rosen, Lee
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - complications; Aza Compounds - therapeutic use; biodistribution/toxicology and kinase; Dose-Response Relationship, Drug; electrocardiogram (ECG); Electrocardiography - methods; Fluoroquinolones; Granisetron - therapeutic use; Heart Ventricles - pathology; Humans; ICH E14 guidance; Indoles - pharmacokinetics; Indoles - pharmacology; Neoplasms - complications; Neoplasms - drug therapy; phosphatase inhibitors; Placebos; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Quinolines - therapeutic use; Risk; risk assessment; solid tumors; sunitinib (Sutent); Time Factors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-1521

Purpose: To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer. Experimental Design: Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread. Results: Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QT c F) of 5.6 ms [90% confidence interval (CI), 1.9-9.3]. Sunitinib QT c F changes correlated with exposure, but not T max . Maximum mean time-matched, placebo-adjusted QT c F was 9.6 ms (90% CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90% CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QT c F >500 ms. Concomitant granisetron produced no significant QT c F prolongation. Sunitinib-related adverse events were as previously described. Conclusions: Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer. (Clin Cancer Res 2009;15(22):7045–52)