Effects of avitinib on the pharmacokinetics of osimertinib in vitro and in vivo in rats.

Background: Avitinib is one type of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study was to investigate the effect of avitinib on the pharmacokinetics of osimertinib, one FDA approved third-generation TIKI, both in vitro and in vivo.
Methods: The in vitro metabolic stability and inhibitory effect of avitinib on osimertinib were assessed with rat liver microsomes (RLM) to determine its IC ₅₀ values. For the in vivo study, 18 Sprague-Dawley rats were randomly divided into three groups: the avitinib multiple dose group (30 mg/kg avitinib once daily for seven days), the avitinib single dose group (PEG200 once daily for six days and a dose of 30 mg/kg avitinib in PEG200 on day 7) and the control group (equal amounts of PEG200 once daily for seven days). Next, all rats were given osimertinib at a dosage of 10 mg/kg. UPLC/MS-MS was used for the determination of the concentration of osimertinib in plasma.
Results: In vitro analysis revealed that the IC ₅₀ value of osimertinib in rat liver microsomes was 27.6 μM. When rats were pretreated with avitinib, the values of AUC and MRT of the osimertinib were increased, and its C _max and T _max were significantly extended, whereas the values of CLz/F were significantly decreased (P < 0.05).
Conclusions: Both in vitro and in vivo results demonstrated that a drug-drug interaction between avitinib and osimertinib occurred and more attention should be paid when avitinib and osimertinib are synchronously administered in clinic.
Key Points: SIGNIFICANT FINDINGS OF THE STUDY: Osimertinib is the only market available third-generation EGFR-TKI and it has been reported that some drugs could have drug-drug interactions with it.
What This Study Adds: For the first time, we systematically investigated the effect of avitinib, one newly developed third-generation EGFR-TKI, on the pharmacokinetics of osimertinib both in vitro and in vivo using a rat model.
(© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)