PURPOSE: QT assessment of oncology drugs is generally challenging because they are genotoxic and, of necessity,they require multisite evaluation in cancer patients. Lenvatinib is not genotoxic, therefore, this thorough QT (TQT)study with lenvatinib, a multityrosine kinase inhibitor, was undertaken utilizing healthy volunteers and concentration effect modeling to project the TQT effect at high plasma levels. METHODS:Fifty-two healthy subjects randomly received single doses of lenvatinib 32 mg, placebo, or moxifloxacin 400 mg in a three-way crossover study. Serial electrocardiograms were recorded, and the effect on placebo corrected change-from-baseline QTcF (ΔΔQTcF) was evaluated. The relationship between lenvatinib plasma concentrations and QTcF was analyzed with linear mixed effects modeling. RESULTS: L envatinib mildly lowered the heart rate by 5–8 bpm during the first 12 h after dosing. ΔΔQTcF was shortened with a peak effect of −5.72 ms (90 % confidence interval (90 % CI) −7.76 to −3.69 ms) at 6 h postdosing.The upper bound of mean ΔΔQTcF did not exceed 2 ms at any time point postdosing. A concentration-dependent effect of lenvatinib on ΔΔQTcF was identified with an estimated population intercept of −2.96 ms (90 % CI −4.49 to−1.43 ms; P = 0.0016) and a negative slope of −0.0045(90 % CI −4.49 to −1.43) ms per ng/mL, respectively. The safety profile after a single dose of lenvatinib was acceptable,with adverse events (AEs) of mild-to-moderate severity and no serious AEs. CONCLUSIONS: L envatinib had no clinically relevant effect on the QTc interval. Concentration-effect modeling supports the lack of QTc prolongation at high plasma concentrations.
RCT Entities:
PURPOSE: QT assessment of oncology drugs is generally challenging because they are genotoxic and, of necessity,they require multisite evaluation in cancerpatients. Lenvatinib is not genotoxic, therefore, this thorough QT (TQT)study with lenvatinib, a multityrosine kinase inhibitor, was undertaken utilizing healthy volunteers and concentration effect modeling to project the TQT effect at high plasma levels. METHODS: Fifty-two healthy subjects randomly received single doses of lenvatinib 32 mg, placebo, or moxifloxacin 400 mg in a three-way crossover study. Serial electrocardiograms were recorded, and the effect on placebo corrected change-from-baseline QTcF (ΔΔQTcF) was evaluated. The relationship between lenvatinib plasma concentrations and QTcF was analyzed with linear mixed effects modeling. RESULTS: L envatinib mildly lowered the heart rate by 5–8 bpm during the first 12 h after dosing. ΔΔQTcF was shortened with a peak effect of −5.72 ms (90 % confidence interval (90 % CI) −7.76 to −3.69 ms) at 6 h postdosing.The upper bound of mean ΔΔQTcF did not exceed 2 ms at any time point postdosing. A concentration-dependent effect of lenvatinib on ΔΔQTcF was identified with an estimated population intercept of −2.96 ms (90 % CI −4.49 to−1.43 ms; P = 0.0016) and a negative slope of −0.0045(90 % CI −4.49 to −1.43) ms per ng/mL, respectively. The safety profile after a single dose of lenvatinib was acceptable,with adverse events (AEs) of mild-to-moderate severity and no serious AEs. CONCLUSIONS: L envatinib had no clinically relevant effect on the QTc interval. Concentration-effect modeling supports the lack of QTc prolongation at high plasma concentrations.
Authors: Ricardo Costa; Benedito A Carneiro; Sunandana Chandra; Sachin G Pai; Young Kwang Chae; Jason B Kaplan; Hannah B Garrett; Mark Agulnik; Peter A Kopp; Francis J Giles Journal: Drug Des Devel Ther Date: 2016-02-29 Impact factor: 4.162