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

Abstract

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. Sunitinibrelated 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. The QT interval represents the duration of ventricular depolarization and repolarization, and is measured with an electrocardiogram (ECG) at the beginning of the QRS interval to the end of the T wave. Key factors affecting QT interval include heart rate, autonomic tone, age, gender, time of day, electrolyte disturbances, and food. Certain pharmacologic therapeutic agents also delay cardiac repolarization and prolong QT interval; these effects are exacerbated by drug-drug interactions (1). These agents therefore increase the risk of cardiac arrhythmias, including torsade de pointes, which can degenerate into ventricular fibrillation, leading to sudden death. Consequently, evaluation of potential cardiac effects, including those on the cardiac conduction system, is a consideration in designing appropriate clinical trials to assess an agent's risk to patients, assess a compound's overall safety, and provide guidance for the clinical management of any effect.According to International Conference on Harmonization E14 guidance, all drugs must undergo a formal clinical evaluation early in clinical development to assess the potential for QT/ QT c prolongation (2). Typically, a single dedicated trial (a thorough QT/QT c trial; TQT) is included in the drug development program and is conducted in healthy volunteers at doses higher than those clinically administered (e.g., "worst case scenario") to characterize dose-response. A TQT should also be randomized and blinded. The use of a placebo control, as well as a concurrent positive control group, is important to rule out non-drug effects and to establish the sensitivity of the trial to detect a known QT interval effect. However...

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