Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects.

Abstract

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. This was an open-label, two-period, fixed-sequence study. Fifteen healthy adult subjects received a single oral dose of neratinib 240mg (Period 1), followed by a washout period, then oral lansoprazole 30mg once daily for 7days and a single dose of neratinib 240mg on Day 5 (Period 2). Pharmacokinetic sampling was performed for 72h 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%. Neratinib geometric least-squares mean (LSM) Cmax was reduced from 84.5ngml-1 with neratinib alone to 24.5ngml-1 with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC0-t was 1478ngml-1 h with neratinib vs. 426ngml-1 h with neratinib plus lansoprazole, and geometric LSM AUC0-inf was 1557ngml-1 h vs. 542ngml-1 h, respectively. Mean t½ was similar with both treatments (approximately 14h). Geometric mean ratios 90% confidence intervals for AUC0-t , AUC0-inf and Cmax fell outside the prespecified equivalence range (80.0-125.0%). Treatment-emergent adverse events, all mild, were reported by five (33%) subjects. Coadministration of lansoprazole with neratinib reduced the rate and extent of neratinib exposure in healthy subjects.