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

Abstract

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.

Fig. 1

Study design. a For Day 1, treatment sequences 1 and 2 were grouped together and labeled as the placebo_moxi group, while treatment sequences 3 and 4 were grouped together and labeled as the moxifloxacin (moxi) group. For Days 2 through 9, treatment sequences 1 and 3 were grouped together and labeled as the placebo_paz group, while treatment sequences 2 and 4 were grouped together and labeled as the pazopanib (paz) group. ^b CONSORT diagram describing patient populations. ^aPatients may be included in >1 category. ^bOne additional patient who was excluded is captured in the intent-to-treat (ITT) population. ^cAn additional 2 patients who had Holter problems on Day 1 were excluded from the evaluable population and are not captured here. AE adverse event PK pharmacokinetics

Fig. 2

Least-squares mean difference in QTc change from baseline for pazopanib-treated patients versus placebo. a Fridericia-corrected QT (QTcF); b Bazett-corrected QT (QTcB); c individualized correction (QTci). Data points and 90 % confidence intervals (CI) are shown in ms. Squares indicate the mean difference in QTc for the evaluable population (n = 65); circles indicate the mean difference in QTc for the intent-to-treat population (n = 96)

Fig. 3

Median plasma concentration–time profiles of pazopanib and its 3 major metabolites (all n = 46) on Day 9, after 800-mg pazopanib once daily on Days 2 through 8 and after 1,600-mg pazopanib with food on Day 9

Fig. 4

Relationship between changes from baseline in Fridericia-corrected QT (QTcF) interval and heart rate and plasma concentrations of study drugs. a, b Boxes in each figure panel display the 90th percentile (upper whisker), the 75th percentile (upper border), median (middle line), 25th percentile (lower border), and the 10th percentile (lower whisker) of the placebo-corrected change from baseline in QTcF values within each plasma concentration range. The broken line in the center of the graph indicates the median change in QTcF. The upper solid line represents the 90th percentile QTcF change, and the lower broken line represents the 10th percentile QTcF change across patients. The thick solid lines at the bottom of the graph represent the plasma concentration range of each quintile. c Boxes display the 90th percentile (upper whisker), the 75th percentile (upper border), median (middle line), 25th percentile (lower border), and the 10th percentile (lower whisker) of the change from baseline in heart rate values within each plasma concentration range. The broken line in the center of the graph indicates the median change in heart rate. The upper solid line represents the 90th percentile heart rate change, and the lower broken line represents the 10th percentile heart rate change across patients. The thick solid lines at the bottom of the graph represent the plasma concentration range of each quintile