Population pharmacokinetic modeling of pyrotinib in patients with HER2-positive advanced or metastatic breast cancer

Objective Pyrotinib, a novel oral irreversible dual pan-ErbB tyrosine kinase inhibitor (TKI), has been approved in China for the treatment of HER2-positive advanced or metastatic breast cancer. This study aimed to conduct a population pharmacokinetics (PK) analysis of pyrotinib and to evaluate the impact of certain HER2-positive breast cancer patient characteristics on pyrotinib’s PK. Method A total of 1152 samples, provided by 59 adult female patients from two phase I clinical trials, were analyzed by nonlinear mixed-effects modeling. Monte Carlo simulation was conducted to assess the impact of covariates following exposure to pyrotinib. Results The PK of pyrotinib was adequately described by a one-compartment model with first-order absorption and elimination. Patient’s age and total protein levels can affect pyrotinib’s apparent volume of distribution, and concomitant use of montmorillonite powder had significant effects on the bioavailability of pyrotinib. No PK interactions were observed between capecitabine and pyrotinib. Conclusion In this study, a population PK model of pyrotinib was developed to determine the influence of patient characteristics on the PK of pyrotinib. While patient age and total protein levels can significantly affect the apparent distribution volume of pyrotinib, the magnitude of the impact was limited, thus no dosage adjustment was recommended. Furthermore, concomitant use of montmorillonite powder for diarrhea can decrease the bioavailability of pyrotinib by 50.3%.