Ying Zhenzhen, Wei Jingyao, Liu Ruijuan, Zhao Fang, Yu Yifang, Tian Xin
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou 450052, China.
Int J Anal Chem. 2020 Dec 28;2020:8814214. doi: 10.1155/2020/8814214. eCollection 2020.
Osimertinib is a novel oral, potent, and irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for treatment of advanced T790M mutation-positive advanced non-small cell lung cancer, which is commonly combined with ginsenoside Rg3 in clinic to enhance the efficacy and minimize adverse reactions. In the present study, a highly sensitive UPLC-MS/MS method was established and validated for analysis of osimertinib in rat plasma according to US FDA guideline. Separation was performed on a C18 (2.1 × 50 mm, 2.6 m) column using a gradient elution of ammonium formate (10 mM) with 0.1% formic acid buffer (A) and ACN (B) at a flow rate of 0.2 mL/min. Detection was carried out on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization in the MRM mode. The method was validated over a concentration range of 1-400 ng/mL for osimertinib. The intra- and interday accuracy and precision values were within ±15%. No significant degradation occurred under the experimental conditions in stability assays. There was a further investigation on the effects of multiple doses of ginsenoside Rg3 on the pharmacokinetics of osimertinib in rats for the first time. The results implied that osimertinib exhibited a slow absorption and moderate-rate elimination in rats following oral administration. Coadministeration with ginsenoside Rg3 (5 mg/kg, 7 days, ) may have no effect on the pharmacokinetics of osimertinib in rats. The results provide a reference for the clinical concomitant medications of Rg3 and osimertinib.
奥希替尼是一种新型口服、强效且不可逆的表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），用于治疗晚期T790M突变阳性的晚期非小细胞肺癌，临床上常与人参皂苷Rg3联合使用以提高疗效并将不良反应降至最低。在本研究中，根据美国食品药品监督管理局（US FDA）指南，建立并验证了一种高灵敏度的超高效液相色谱-串联质谱（UPLC-MS/MS）方法，用于分析大鼠血浆中的奥希替尼。采用C18（2.1×50 mm，2.6 µm）色谱柱，以0.1%甲酸缓冲液（A）和乙腈（B）的10 mM甲酸铵梯度洗脱，流速为0.2 mL/min进行分离。在配备电喷雾电离的三重四极杆串联质谱仪上以多反应监测（MRM）模式进行检测。该方法在1-400 ng/mL的奥希替尼浓度范围内进行了验证。日内和日间的准确度和精密度值均在±15%以内。在稳定性试验的实验条件下未发生明显降解。首次进一步研究了多剂量人参皂苷Rg3对大鼠体内奥希替尼药代动力学的影响。结果表明，奥希替尼经口服给药后在大鼠体内吸收缓慢且消除速率适中。与人参皂苷Rg3（5 mg/kg，7天）共同给药可能对大鼠体内奥希替尼的药代动力学没有影响。这些结果为Rg3和奥希替尼的临床联合用药提供了参考。
