Selpercatinib (LOXO‐292) is a selective and potent RET inhibitor. A highly sensitive, rapid and specific high‐performance liquid chromatography with tandem mass spectrometry (LC–MS/MS) method for quantification of selpercatinib in rat plasma is reported. The method was validated in terms of selectivity, linearity, accuracy and precision, extraction recovery and matrix effect, stability and carryover as per the US Food and Drug Administration guidelines for bioanalytical method validation. Selpercatinib was detected by an electrospray ionization interface under selective reaction monitoring conditions in the positive ion mode. The calibration curve was linear over the concentration range from 1 to 2000 ng/ml with r² = 0.9951. The intra‐ and inter‐batch accuracy values ranged from 97.45 to 100.97% and from 98.70 to 100.74% with coefficients of variation of 2.45–6.99% and 5.89–7.99%, respectively. The extraction recovery and IS‐normalized matrix factor were acceptable for the bioanalysis of selpercatinib. Additionally, selpercatinib was found to be stable under the detected conditions. It showed linear pharmacokinetic characteristics following oral administration to rats at 2.0–18.0 mg/kg. The results showed that the novel method for detecting selpercatinib in rat plasma could be successfully applied for quantification of selpercatinib in biosamples from nonclinical studies.

中文翻译：

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血浆中RET激酶抑制剂selpercatinib的测定及其在药代动力学研究中的应用

Selpercatinib（LOXO-292）是一种选择性有效的RET抑制剂。据报道，采用高灵敏度，快速，特异的高效液相色谱-串联质谱（LC-MS / MS）方法对大鼠血浆中的selpercatinib进行定量。根据美国食品和药物管理局生物分析方法验证指南，在选择性，线性，准确性和精密度，提取回收率和基质效应，稳定性和残留率等方面对方法进行了验证。在正离子模式下的选择性反应监测条件下，通过电喷雾电离界面检测到Selpercatinib。校准曲线在1至2000 ng / ml的浓度范围内呈线性关系，r ² = 0.9951。批内和批间精度值的范围分别为97.45至100.97％和98.70至100.74％，变异系数分别为2.45–6.99％和5.89–7.99％。提取回收率和IS归一化基质因子可用于selpercatinib的生物分析。另外，发现selpercatinib在检测到的条件下是稳定的。在以2.0–18.0 mg / kg的大鼠口服给药后，它显示出线性的药代动力学特征。结果表明，用于检测大鼠血浆中selpercatinib的新方法可以成功地用于定量来自非临床研究的生物样品中的selpercatinib。