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 μm) 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, i.g.) 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.

中文翻译：

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UPLC-MS / MS法测定大鼠血浆中奥西替尼的用途：在研究人参皂苷Rg3对奥西替尼药代动力学的影响中的应用

Osimertinib是一种新型的口服，有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，在临床上通常与人参皂甙Rg3联合使用以增强功效并最大程度地减少不良反应。在本研究中，根据美国FDA指南建立了高度灵敏的UPLC-MS / MS方法，并验证了该方法可用于分析大鼠血浆中的奥西替尼。在C18（2.1×50 mm，  2.6μm）色谱柱，使用甲酸铵（10 mM）和0.1％甲酸缓冲液（A）和乙腈（B）的梯度洗脱液，流速为0.2 mL / min。在配备了电喷雾电离的三重四极杆串联质谱仪上以MRM模式进行检测。对于奥西替尼，该方法在1–400 ng / mL的浓度范围内得到验证。日内和日间的准确度和精密度值在±15％之内。在稳定性测定中的实验条件下没有发生明显的降解。首次对多剂量人参皂苷Rg3对奥西替尼药代动力学的影响进行了进一步的研究。结果表明，口服口服奥西替尼在大鼠中显示出缓慢的吸收和中等速率的消除。与人参皂苷Rg3（5 mg / kg，7天，ig）对奥西替尼在大鼠中的药代动力学可能没有影响。研究结果为Rg3和奥西替尼的临床伴随用药提供了参考。