Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt.
Clin Chim Acta. 2018 Oct;485:298-304. doi: 10.1016/j.cca.2018.07.009. Epub 2018 Jul 10.
Entrectinib (ENC) is a potent orally available anaplastic lymphoma kinase (ALK) inhibitor. In 10 July 2017, biotechnology company (Ignyta) announced that granted orphan drug designation approval was given by the FDA to ENC for "treatment of NTRK fusion-positive solid tumors". A validated LC-MS/MS methodology was developed for ENC quantification in human plasma matrix. The supposed method characterized by high speed, specificity and sensitivity. This established method was applied for metabolic degradation assessment of ENC. Reversed stationary phase (C column) and elution mobile phase (48% 10 mM ammonium formate in HO (pH: 4.2 adjusted by adding few drops of formic acid): 52% ACN) were utilized for chromatographic resolution of ENC and lapatinib as internal standard (IS). Total elution time, flow rate and injection volume were 4 min., 0.25 mL/min., and 5 μL, respectively. Electrospray ionization source was used for ions generation, while positive multiple reactions monitoring (MRM) mode was used for ion analysis. The data of calibration curve of ENC in human plasma was linear in the range of 5-500 ng/mL with correlation coefficient (r) >0.999. LOQ and LOD for ENC were 2.17 ng/mL and 0.71 ng/mL, respectively. Inter-day and intra-day precision and accuracy were 97.52 to 101.83%, and 0.38 to 1.32%, respectively. Intrinsic clearance (Clint) and in vitro half-life (t) were equal to 15.67 mL/min/kg and 9.1 min, respectively. To our knowledge, this is considered the first method for ENC quantification in human plasma and its metabolic degradation assessment.
恩曲替尼（ENC）是一种有效的口服可利用的间变性淋巴瘤激酶（ALK）抑制剂。2017 年 7 月 10 日，生物技术公司（Ignyta）宣布，美国食品和药物管理局（FDA）授予 ENC 孤儿药指定批准，用于“治疗 NTRK 融合阳性实体瘤”。建立了一种用于人血浆基质中 ENC 定量的经验证的 LC-MS/MS 方法。该方法的特点是速度快、特异性和灵敏度高。该建立的方法被应用于评估 ENC 的代谢降解。反相固定相（C 柱）和洗脱流动相（48%HO 中 10mM 甲酸铵（pH：通过加入少量甲酸调节至 4.2）：52%ACN）被用于色谱分离恩曲替尼和拉帕替尼作为内标（IS）。总洗脱时间、流速和进样量分别为 4min、0.25mL/min 和 5μL。电喷雾电离源用于离子生成，而正多重反应监测（MRM）模式用于离子分析。ENC 在人血浆中的校准曲线数据呈线性，范围为 5-500ng/mL，相关系数（r）>0.999。ENC 的 LOQ 和 LOD 分别为 2.17ng/mL 和 0.71ng/mL。日内和日间精密度和准确度分别为 97.52%至 101.83%和 0.38%至 1.32%。内在清除率（Clint）和体外半衰期（t）分别为 15.67mL/min/kg 和 9.1min。据我们所知，这被认为是第一个用于人血浆中 ENC 定量及其代谢降解评估的方法。
