Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects.

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 AUC , AUC , and peak plasma concentrations (C ) 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) C was reduced from 84.5 ng ml with neratinib alone to 24.5 ng ml with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC was 1478 ng ml  h with neratinib vs. 426 ng ml  h with neratinib plus lansoprazole, and geometric LSM AUC was 1557 ng ml  h vs. 542 ng ml  h, respectively. Mean t was similar with both treatments (approximately 14 h). Geometric mean ratios 90% confidence intervals for AUC , AUC and C fell 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.