The influence of verapamil on the pharmacokinetics of the pan-HER tyrosine kinase inhibitor neratinib in rats: the role of P-glycoprotein-mediated efflux

Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has been approved for the treatment of HER2-positive (HER2 + ) early-stage and brain metastatic breast cancer. Thus far, the pharmacology effects and pharmacodynamics of neratinib have been well studied. However, the disposition of neratinib and its influencing factors in vivo remain unclear. P-glycoprotein (P-gp), one of the most extensively studied transporters, substantially restricts penetration of drugs into the body or deeper compartments (i.e., blood-brain barrier, BBB), regarding drug resistance and drug-drug interactions. Thereby, the aim of this study was to investigate the influence of verapamil (a P-gp inhibitor) on the pharmacokinetics of neratinib in rats. Here, we have established a high specific, selective and sensitive ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify plasma concentrations of neratinib in rats. Pharmacokinetic results showed that verapamil significantly increased the system exposure of neratinib, as C max increased by 2.09-fold and AUC 0 − t increased by 1.64-fold, respectively. Additionally, the in vitro transport of neratinib using Madin-Darby canine kidney II (MDCK II) and MDCK-MDR1 cell line models. As a result, the net flux ratio was over than 2 and decreased over 50% by verapamil, suggesting that probably neratinib was a substrate of P-gp. Hence, coadministration of P-gp inhibitors might be indispensable for neratinib in the treatment of breast cancer patients, especially for brain metastases. These findings may support the further clinical development and application of neratinib.