Reyes-Ortega Felisa, Qiu Fiona, Schneider-Futschik Elena K
Clinical Research Unit, Pathology Anatomic Building, University Hospital Reina Sofía, Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain.
Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia.
ACS Pharmacol Transl Sci. 2020 Sep 11;3(5):987-996. doi: 10.1021/acsptsci.0c00103. eCollection 2020 Oct 9.
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 ( = 0.9865105), ivacaftor-M1 ( = 0.9852684), ivacaftor-M6 ( = 0.9911764), tezacaftor ( = 0.98742470), and elexacaftor ( = 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.
依伐卡托-替扎卡托和依伐卡托-替扎卡托-艾列卡托是新型突破性囊性纤维化（CF）药物组合，可直接调节导致CF疾病状态的缺陷性CF跨膜电导调节蛋白（CFTR）的活性和转运。目前，在医院环境中，对于这些极其昂贵但能救命的药物，尚无治疗药物监测检测方法。我们开发并验证了一种使用多反应监测质谱法（MRM/MS）在人血浆中定量依伐卡托及其代谢物、替扎卡托和艾列卡托的快速、精确的新方法。MRM/MS分析方法在人血浆中依伐卡托、依伐卡托-M1、依伐卡托-M6、替扎卡托和艾列卡托的浓度范围为0.0025 - 1μg/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0.01μg/mL时。流动相由[乙腈/水]/0.1%甲酸（70:30 v/v）组成，流速为0.5 mL/min，在人血浆中依伐卡托（r = 0.9865105）、依伐卡托-M1（r = 0.9852684）、依伐卡托-M6（r = 0.9911764）、替扎卡托（r = 0.98742470）和艾列卡托（r = 0.9897608）的浓度范围为0.0025 - 1μg/mL时观察到线性相关性。所报道的方法能够在人血浆低浓度下准确定量依伐卡托、依伐卡托-M1、依伐卡托-M6、替扎卡托和艾列卡托。我们已经建立了一种经济高效且及时的方法，用于在人血浆中测量依伐卡托及其代谢物以及有或没有艾列卡托的替扎卡托，适用于医院环境或临床试验中的高通量应用。
