A Single-Dose, Crossover, Placebo- and Moxifloxacin-Controlled Study to Assess the Effects of Neratinib (HKI-272) on Cardiac Repolarization in Healthy Adult Subjects

Purpose: Neratinib is an orally administered, small-molecule, irreversible pan-ErbB inhibitor in development for the treatment of ErbB2-positive breast cancer. This study assessed the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization, in accordance with current regulatory guidance. Experimental Design: This was a two-part study in healthy subjects. In part 1, subjects were randomized to receive placebo, 400 mg moxifloxacin, or 240 mg neratinib (therapeutic dose) following a high-fat meal. In part 2, after a washout period, subjects received placebo plus 400 mg ketoconazole or 240 mg neratinib plus ketoconazole (supratherapeutic dose). ANOVA was used to compare the baseline-adjusted QTc interval for neratinib with that of placebo (reference), and for neratinib plus ketoconazole with that of placebo plus ketoconazole (reference). Pharmacokinetic/pharmacodynamic analyses and categorical summaries of interval data were done. Assay sensitivity was evaluated by the effect of moxifloxacin on QTc compared with placebo. Results: Sixty healthy subjects were enrolled in this study. The upper bounds of the 90% confidence interval for baseline-adjusted QTcN (population-specific corrected QT) were <= 10 milliseconds greater than the corresponding reference at all postdose time points under conditions of both therapeutic and supratherapeutic plasma concentrations of neratinib. Pharmacokinetic/pharmacodynamic analysis revealed no relationship between neratinib concentrations and QTc interval. No subjects had QTcI, QTcF, or QTcN intervals >450 milliseconds or change from baseline >30 milliseconds. Moxifloxacin produced a significant increase in QTcN compared with placebo (P < 0.05). Conclusions: Therapeutic and supratherapeutic plasma concentrations of neratinib do not prolong the QTc interval in healthy subjects. Clin Cancer Res; 16(15); 4016-23. (C) 2010 AACR.