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. 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.
How strong is the evidence?
Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 48 participants or records.
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