Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects

Abstract

Aims: To evaluate the effect of lansoprazole, a proton-pump inhibitor, on the absorption, pharmacokinetics, and safety of neratinib, a pan-HER tyrosine kinase inhibitor, in healthy subjects. Methods: This was an open-label, two-period, fixed-sequence study. Fifteen healthy adult subjects received a single oral dose of neratinib 240 mg (Period 1), followed by a washout period, then oral lansoprazole 30 mg once daily for 7 days and a single dose of neratinib 240 mg on Day 5 (Period 2). Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Plasma neratinib concentration–time data were analysed using noncompartmental methods. Geometric mean ratios for AUC0–t, AUC0–inf, and peak plasma concentrations (Cmax) for neratinib plus lansoprazole vs. neratinib were used to assess the magnitude of the drug–drug interaction if the 90% confidence intervals were outside 80.00–125.00%. Results: Neratinib geometric least-squares mean (LSM) Cmaxwas reduced from 84.5 ng ml−1with neratinib alone to 24.5 ng ml−1with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC0–twas 1478 ng ml−1 h with neratinib vs. 426 ng ml−1 h with neratinib plus lansoprazole, and geometric LSM AUC0–infwas 1557 ng ml−1 h vs. 542 ng ml−1 h, respectively. Mean t½was similar with both treatments (approximately 14 h). Geometric mean ratios 90% confidence intervals for AUC0–t, AUC0–infand Cmaxfell outside the prespecified equivalence range (80.0–125.0%). Treatment-emergent adverse events, all mild, were reported by five (33%) subjects. Conclusions: Coadministration of lansoprazole with neratinib reduced the rate and extent of neratinib exposure in healthy subjects.