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Multiple Reaction Monitoring Mass Spectrometry for the Drug Monitoring of Ivacaftor, Tezacaftor, and Elexacaftor Treatment Response in Cystic Fibrosis: A High-Throughput Method
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-09-11 , DOI: 10.1021/acsptsci.0c00103 Felisa Reyes-Ortega 1 , Fiona Qiu 2 , Elena K Schneider-Futschik 2
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-09-11 , DOI: 10.1021/acsptsci.0c00103 Felisa Reyes-Ortega 1 , Fiona Qiu 2 , Elena K Schneider-Futschik 2
Affiliation
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Ivacaftor–tezacaftor and ivacaftor–tezacaftor–elexacaftor are new breakthrough cystic fibrosis (CF) drug combinations that directly modulate the activity and trafficking of the defective CF transmembrane conductance regulator protein (CFTR) underlying the CF disease state. Currently, in the hospital setting, there are no therapeutic drug monitoring assays for these very expensive, albeit, life-saving drugs. A rapid and precise novel method for the quantification of ivacaftor, its metabolites, tezacaftor, and elexacaftor, in human plasma was developed and validated using multiple reaction monitoring mass spectrometry (MRM/MS). The MRM/MS analytical method was validated at a concentration range of 0.0025–1 μg/mL for ivacaftor, ivacaftor-M1, ivacaftor-M6, tezacaftor, and elexacaftor in human plasma. The method displayed good accuracy (90.62–94.51%) and reproducibility (99.91–100%) including at low concentrations 0.01 μg/mL. With a mobile phase consisting of [acetonitrile/water]/0.1% formic acid (70:30 v/v) at a flow rate of 0.5 mL/min, a linear correlation was observed over a concentration range of 0.0025–1 μg/mL in human plasma for ivacaftor (R2 = 0.9865105), ivacaftor-M1 (R2 = 0.9852684), ivacaftor-M6 (R2 = 0.9911764), tezacaftor (R2 = 0.98742470), and elexacaftor (R2 = 0.9897608). The reported method can accurately quantify ivacaftor, ivacaftor-M1, ivacaftor-M6, tezacaftor, and elexacaftor at low concentrations in human plasma. We have established a cost-efficient and timely method for measuring ivacaftor, its metabolites, and tezacaftor with or without elexacaftor in human plasma suitable for high-throughput applications in the hospital settings or clinical trials.
中文翻译：
用于囊性纤维化中 Ivacaftor、Tezacaftor 和 Elexacaftor 治疗反应药物监测的多重反应监测质谱法：一种高通量方法
Ivacaftor-tezacaftor 和 ivacaftor-tezacaftor-elexacaftor 是新的突破性囊性纤维化（CF）药物组合，可直接调节 CF 疾病状态下有缺陷的 CF 跨膜电导调节蛋白（CFTR）的活性和运输。目前，在医院环境中，还没有对这些非常昂贵但可以救命的药物进行治疗药物监测分析。使用多反应监测质谱法 (MRM/MS) 开发并验证了一种快速、精确的定量人血浆中 ivacaftor 及其代谢物 tezacaftor 和 elexacaftor 的新方法。 MRM/MS 分析方法在人血浆中的 ivacaftor、ivacaftor-M1、ivacaftor-M6、tezacaftor 和 elexacaftor 浓度范围为 0.0025–1 μg/mL 时得到验证。该方法显示出良好的准确度 (90.62–94.51%) 和重现性 (99.91–100%)，包括在低浓度 0.01 μg/mL 下。使用由 [乙腈/水]/0.1% 甲酸 (70:30 v/v) 组成的流动相，流速为 0.5 mL/min，在 0.0025–1 μg/mL 的浓度范围内观察到线性相关性人血浆中ivacaftor( R 2 = 0.9865105)、ivacaftor-M1( R 2 = 0.9852684)、ivacaftor-M6( R 2 = 0.9911764)、tezacaftor( R 2 = 0.98742470)和elexacaftor( R 2 = 0.9897608)。报道的方法可以准确定量人血浆中低浓度的 ivacaftor、ivacaftor-M1、ivacaftor-M6、tezacaftor 和 elexacaftor。 我们建立了一种经济有效且及时的方法，用于测量人血浆中的 ivacaftor、其代谢物和 tezacaftor（含或不含 elexacaftor），适合医院环境或临床试验中的高通量应用。
更新日期：2020-10-11
中文翻译：
用于囊性纤维化中 Ivacaftor、Tezacaftor 和 Elexacaftor 治疗反应药物监测的多重反应监测质谱法：一种高通量方法
Ivacaftor-tezacaftor 和 ivacaftor-tezacaftor-elexacaftor 是新的突破性囊性纤维化（CF）药物组合，可直接调节 CF 疾病状态下有缺陷的 CF 跨膜电导调节蛋白（CFTR）的活性和运输。目前，在医院环境中，还没有对这些非常昂贵但可以救命的药物进行治疗药物监测分析。使用多反应监测质谱法 (MRM/MS) 开发并验证了一种快速、精确的定量人血浆中 ivacaftor 及其代谢物 tezacaftor 和 elexacaftor 的新方法。 MRM/MS 分析方法在人血浆中的 ivacaftor、ivacaftor-M1、ivacaftor-M6、tezacaftor 和 elexacaftor 浓度范围为 0.0025–1 μg/mL 时得到验证。该方法显示出良好的准确度 (90.62–94.51%) 和重现性 (99.91–100%)，包括在低浓度 0.01 μg/mL 下。使用由 [乙腈/水]/0.1% 甲酸 (70:30 v/v) 组成的流动相，流速为 0.5 mL/min，在 0.0025–1 μg/mL 的浓度范围内观察到线性相关性人血浆中ivacaftor( R 2 = 0.9865105)、ivacaftor-M1( R 2 = 0.9852684)、ivacaftor-M6( R 2 = 0.9911764)、tezacaftor( R 2 = 0.98742470)和elexacaftor( R 2 = 0.9897608)。报道的方法可以准确定量人血浆中低浓度的 ivacaftor、ivacaftor-M1、ivacaftor-M6、tezacaftor 和 elexacaftor。 我们建立了一种经济有效且及时的方法，用于测量人血浆中的 ivacaftor、其代谢物和 tezacaftor（含或不含 elexacaftor），适合医院环境或临床试验中的高通量应用。
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