Lin Jiahui, Jiang Aiting, Zheng Juntao, Wu Jingjing, Li Hao, Cai Shirong, He Yulong, Chen Xiao, Zhong Guoping, Tang Ke-Jing, Zhang Xinhua, Xia Yanzhe
Department of Pharmacy, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
Front Pharmacol. 2025 Jan 6;15:1506931. doi: 10.3389/fphar.2024.1506931. eCollection 2024.
Ripretinib, a broad-spectrum tyrosine kinase inhibitor, has been approved for the treatment of advanced gastrointestinal stromal tumors in adult patients. Clinical studies have shown that higher exposure of ripretinib correlates with improved efficacy, highlighting the potential clinical significance of therapeutic drug monitoring. In this study, a simple and stable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was attempted to be established and validated for pharmacokinetic studies of ripretinib and its metabolite DP-5439 and therapeutic drug monitoring in human plasma.
Ripretinib and DP-5439 were separated by chromatography using a Thermofisher Hypersil GOLD C18 HPLC column. The mobile phase for gradient elution is composed of 0.1% formic acid in water and acetonitrile. Multiple reaction monitoring was implemented along with electrospray ionization positive mode for detection. The ion pairs of ripretinib, DP-5439 and internal standard D8-ripretinib were m/z 510.1→m/z 417, m/z 496.11→m/z 402.9 and m/z 518.15→m/z 420, respectively. Plasma samples from ripretinib-treated patients of our hospital were collected for pharmacokinetic analysis.
Ripretinib and DP-5439 demonstrated a strong linear relationship over 10-5,000 μg/L ( > 0.99). Accuracy, precision, specificity, recoveries, matrix effect, stability, and dilution effect were all validated and found to meet the required criteria. Following validation, the method was utilized to determine plasma samples from patients treated with ripretinib. The median steady-state trough concentrations (C, range) were 398.50 (66.98 ∼ 1,458.91) μg/L for ripretinib and 654.74 (30.71 ∼ 1,522.48) μg/L for DP-5439, with a total median concentration of 1,129.46 (140.95 ∼ 2,981.39) μg/L in patients receiving ripretinib at 150 mg once daily. Meanwhile, using the established methods, the study conducted pharmacokinetics studies on four patients with ripretinib and DP-5439.
This study developed and validated a robust LC-MS/MS method for determining ripretinib and its metabolite DP-5439 in human plasma. Furthermore, the practicality of this method in clinical sample analysis was demonstrated. This approach can serve as an effective tool for the pharmacokinetics analysis and therapeutic drug monitoring in patients treated with ripretinib.
瑞派替尼是一种广谱酪氨酸激酶抑制剂，已被批准用于治疗成年患者的晚期胃肠道间质瘤。临床研究表明，瑞派替尼的暴露量越高，疗效越好，这突出了治疗药物监测的潜在临床意义。在本研究中，尝试建立并验证一种简单、稳定的液相色谱-串联质谱（LC-MS/MS）方法，用于瑞派替尼及其代谢产物DP-5439的药代动力学研究以及人血浆中的治疗药物监测。
使用Thermofisher Hypersil GOLD C18高效液相色谱柱通过色谱法分离瑞派替尼和DP-5439。梯度洗脱的流动相由含0.1%甲酸的水和乙腈组成。采用多反应监测并结合电喷雾电离正模式进行检测。瑞派替尼、DP-5439和内标D8-瑞派替尼的离子对分别为m/z 510.1→m/z 417、m/z 496.11→m/z 402.9和m/z 518.15→m/z 420。收集我院接受瑞派替尼治疗患者的血浆样本进行药代动力学分析。
瑞派替尼和DP-5439在10 - 5000μg/L范围内呈现出很强的线性关系（>0.99）。准确性、精密度、特异性、回收率、基质效应、稳定性和稀释效应均经过验证，结果符合要求标准。验证后，该方法用于测定接受瑞派替尼治疗患者的血浆样本。瑞派替尼的中位稳态谷浓度（C，范围）为398.50（66.98 ∼ 1458.91）μg/L，DP-5439为654.74（30.71 ∼ 1522.48）μg/L，在每日一次接受150mg瑞派替尼治疗的患者中，总中位浓度为1129.46（140.95 ∼ 2981.39）μg/L。同时，使用所建立的方法，对4例患者进行了瑞派替尼和DP-5439的药代动力学研究。
本研究开发并验证了一种可靠的LC-MS/MS方法，用于测定人血浆中的瑞派替尼及其代谢产物DP-5439。此外，证明了该方法在临床样本分析中的实用性。该方法可作为接受瑞派替尼治疗患者药代动力学分析和治疗药物监测的有效工具。
