Department of Thoracic Surgery, Beijing Hospital, National Center of Gerontology, Beijing, China.
Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, China.
Thorac Cancer. 2020 Oct;11(10):2775-2781. doi: 10.1111/1759-7714.13587. Epub 2020 Aug 19.
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.
The in vitro metabolic stability and inhibitory effect of avitinib on osimertinib were assessed with rat liver microsomes (RLM) to determine its IC 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.
In vitro analysis revealed that the IC 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 and T were significantly extended, whereas the values of CLz/F were significantly decreased (P < 0.05).
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.
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.
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.
阿维替尼是一种用于治疗表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）的第三代 EGFR 酪氨酸激酶抑制剂（TKI）。本研究旨在探讨阿维替尼对已获批的第三代 TKI 奥希替尼的体内外药代动力学的影响。
采用大鼠肝微粒体（RLM）评估阿维替尼对奥希替尼的体外代谢稳定性和抑制作用，以确定其 IC 值。在体内研究中，将 18 只 Sprague-Dawley 大鼠随机分为三组：阿维替尼多次剂量组（30mg/kg 阿维替尼每日一次，连续 7 天）、阿维替尼单次剂量组（PEG200 每日一次，连续 6 天，第 7 天给予 30mg/kg 阿维替尼）和对照组（PEG200 每日一次，连续 7 天）。所有大鼠均给予奥希替尼 10mg/kg。采用 UPLC/MS-MS 测定血浆中奥希替尼的浓度。
体外分析显示，奥希替尼在大鼠肝微粒体中的 IC 值为 27.6μM。当大鼠预先给予阿维替尼时，奥希替尼的 AUC 和 MRT 值增加，C 和 T 显著延长，而 CLz/F 值显著降低（P<0.05）。
体内外研究结果均表明，阿维替尼与奥希替尼之间存在药物相互作用，在临床同步使用阿维替尼和奥希替尼时应引起更多关注。
