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.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…QTc prolongation was common (37%) in patients with hepatic impairment treated with bosutinib,10 but this was not seen in other smaller studies 11, 12. QTc prolongation was infrequent or absent with afatinib, crizotinib, ceritinib, dovitinib, imatinib, lapatinib, lenvatinib, nintedanib, pazopanib, and ponatinib 9, 14, 16, 17, 19, 24, 26, 27, 29, 30, 31, 32, 33, 35, 36, 38, 39, 72, 78, 81, 161, 162, 163, 164…”

The contribution of VEGF signalling to fostamatinib‐induced blood pressure elevation

“…In phase II clinical trials, the mean increase in systolic BP seen with fostamatinib is approximately 5 mmHg in patients with rheumatoid arthritis (Weinblatt et al ., ; Genovese et al ., ). However, other VEGFR2 inhibitors show much greater increases in BP in the clinic (value in brackets refer to the mean mmHg increase in systolic BP): cediranib (19, Robinson et al ., ), pazopanib (18, Heath et al ., ), sorafenib (21, Veronese et al ., ), sunitinib (25, Eechoute et al ., ) and vandetanib (12, Mayer et al ., ). Therefore, the comparatively lower increase in BP seen with fostamatinib may reflect the lower inhibition of VEGFR2 at therapeutic levels.…”

Cardiovascular adverse events associated with oral antineoplastic therapy

“…The characterization of the 23 articles showed that the year of publication ranged between 1985 and 2015, with thirteen published in the United States (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) , seven in England (24)(25)(26)(27)(28)(29)(30) and three in other European countries (31)(32)(33) . Regarding the levels of evidence, the following distribution was observed: one level I (27) , seven level II (15,17,20,22,(28)(29)31) , six level III (13,(18)(19)21,23,30) , and nine level IV (11)(12)14,16,24,26,(32)(33) .…”