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

Background: Avitinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used to treat non-small cell lung cancer (NSCLC) with EGFR mutations. This study aimed to investigate how avitinib affects the pharmacokinetics of osimertinib, an FDA-approved third-generation TKI, both in vitro and in vivo.

Methods: We assessed the in vitro metabolic stability and inhibitory effects of avitinib on osimertinib using rat liver microsomes (RLM) to determine the IC50 values. For the in vivo study, 18 Sprague-Dawley rats were randomly assigned to three groups: the avitinib multiple dose group (30 mg/kg avitinib once daily for seven days), the avitinib single dose group (30 mg/kg avitinib on day 7 following six days of PEG200), and a control group (PEG200 alone for seven days). All rats were subsequently administered osimertinib at a dose of 10 mg/kg. Plasma concentrations of osimertinib were determined using UPLC/MS-MS.

Results: The in vitro analysis indicated that the IC50 value of osimertinib in rat liver microsomes was 27.6 μM. In the in vivo study, pretreatment with avitinib resulted in increased AUC and MRT values for osimertinib, while Cmax and Tmax were significantly extended. Additionally, the clearance (CLz/F) of osimertinib was significantly reduced (P < 0.05).

Conclusions: Both in vitro and in vivo findings demonstrated a drug-drug interaction between avitinib and osimertinib, highlighting the need for caution when these agents are co-administered in clinical settings.

Key Points:

Significant Findings: Osimertinib is the only commercially available third-generation EGFR-TKI, and various drugs have been reported to interact with it.
What This Study Adds: This study is the first to systematically investigate the impact of avitinib, a newly developed third-generation EGFR-TKI, on the pharmacokinetics of osimertinib in both in vitro and in vivo rat models.