Objective: To establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for a simultaneous determination of three first-line tyrosine kinase inhibitors (imatinib, dasatinib, and nilotinib) and three first-line triazole antifungal drugs (voriconazole, itraconazole, and posaconazole) in plasma, and to use the method in clinical therapeutic drug monitoring. Methods: 50 μL plasma sample was precipitated with acetonitrile after the addition of 20 μL internal standard clozapine and then diluted for analysis. Welch XB-C18 (2.1 mm×50 mm, 5.0 μm) column was used for chromatographic separation. The mobile phase A was 10 mol·L-1 ammonium formate solution and the mobile phase B was methanol-acetonitrile-isopropanol (7∶1.5∶1.5, containing 0.2% formic acid) with gradient elution at the flow rate of 0.72 mL·min-1. The injection volume was 6 μL and the chromatographic time was 3.5 min. Electrospray ion source, positive ion scanning, and multiple reaction monitoring mode were used for determination. Results: The linear range of the six analytes met the detection requirements and the linear coefficients were greater than 0.997. The RSD of intra- and inter-day assays of each concentration was less than 10.34%. The recoveries were 98.6%-111.6% and the accuracy was 94.3%-109.5%. In addition, 6 patients who received imatinib and voriconazole were collected and measured. The plasma concentrations of imatinib and voriconazole were 0.418-2.697 μg·mL-1 and 0.312-8.725 μg·mL-1, respectively, with significant individual differences. Conclusion: This study successfully establishes a method for simultaneously measuring the plasma concentrations of three first-line tyrosine kinase inhibitors and three first-line triazole antifungal drugs, which can be used in clinical therapeutic drug monitoring.
XIANG Dong, YU Heng-yi, LIU Lu, LI Xi-ping, ZHAO Ting-hui, LI Ning-hong, LIU Dong, GONG Xue-peng
. Simultaneous determination of imatinib, dasatinib, nilotinib, voriconazole, itraconazole and posaconazole concentration in plasma by LC-MS/MS[J]. Chinese Journal of Pharmaceutical Analysis, 2022
, 42(2)
: 271
-278
.
DOI: 10.16155/j.0254-1793.2022.02.11
[1] HOCHHAUS A, BACCARANI M, SILVER RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia [J].Leukemia, 2020, 34(4): 966
[2] DEMETRI GD, WANG Y, WEHRLE E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with Unresectable/Metastatic gastrointestinal stromal tumors [J].J Clin Oncol, 2009, 27(19): 3141
[3] GARCíA-FERRER M, WOJNICZ A, MEJÍA G, et al. Utility of therapeutic drug monitoring of imatinib, nilotinib, and dasatinib in chronic myeloid leukemia: A systematic review and meta-analysis [J].Clin Ther, 2019, 41(12): 2558
[4] 杨华强,张荣环,覃骏, 等. 恶性血液病并发侵袭性真菌病的研究进展 [J].湖北医药学院学报, 2021, 40(1): 101
YANG HQ, ZHANG RH, QIN J, et al. Research progress of hematological malignancies complicated with invasive mycosis [J].J Hubei Univ Med, 2021, 40(1): 101
[5] ZHAO YJ, KHOO AL, TAN G, et al. Network meta-analysis and pharmacoeconomic evaluation of fluconazole, itraconazole, posaconazole, and voriconazole in invasive fungal infection prophylaxis [J].Antimicrob Agents Chemother, 2016, 60(1): 376
[6] JOHN J, LOO A, MAZUR S, et al. Therapeutic drug monitoring of systemic antifungal agents: a pragmatic approach for adult and pediatric patients [J].Expert Opin Drug Metab Toxicol, 2019, 15(11): 881
[7] 泊沙康唑临床应用专家组. 泊沙康唑临床应用专家共识 [J].国际呼吸杂志, 2020, 40(4): 241
Working Group of Expert Consensuson Clinical Use of Posaconazole. Expert consensus on clinical use of posaconazole [J].Int J Respir, 2020, 40(4): 241
[8] CHEN K, ZHANG X, KE X, et al. Individualized medication of voriconazole: a practice guideline of the division of therapeutic drug monitoring, chinese pharmacological society [J].Ther Drug Monit, 2018, 40(6): 663
[9] MIURA M. Therapeutic drug monitoring of imatinib, nilotinib, and dasatinib for patients with chronic myeloid leukemia [J].Biol Pharm Bull, 2015, 38(5): 645
[10] 陈恳,张相林,克晓燕, 等. 《伏立康唑个体化用药指南》解读 [J].临床药物治疗杂志, 2019, 17(3): 47
CHEN K, ZHANG XL, KE XY, et al. Executive summary of the Practice Guideline for Individualized Medication of Voriconazole [J].Clin Med J, 2019, 17(3): 47
[11] LI X, LI W, LI M, et al. Correlation between enzyme multiplied immunoassay technique and high-performance liquid chromatography in the quantification of voriconazole in a paediatric population [J].Scand J Clin Lab Invest, 81(2):121
[12] SAITA T, YAMAMOTO Y, HOSOYA K, et al. An ultra-specific and sensitive sandwich ELISA for imatinib using two anti-imatinib antibodies [J].Anal Chim Acta, 2017, 969: 72
[13] GORDIEN JB, PIGNEUX A, VIGOUROUX S, et al. Simultaneous determination of five systemic azoles in plasma by high-performance liquid chromatography with ultraviolet detection [J].J Pharm Biomed Anal, 2009, 50(5): 932
[14] JENKINS N, BLACK M, SCHNEIDER HG. Simultaneous determination of voriconazole, posaconazole, itraconazole and hydroxy-itraconazole in human plasma using LC-MS/MS [J].Clin Biochem, 2018, 53: 110
[15] KOLLER D, VAITSEKHOVICH V, MBA C, et al. Effective quantification of 11 tyrosine kinase inhibitors and caffeine in human plasma by validated LC-MS/MS method with potent phospholipids clean-up procedure. Application to therapeutic drug monitoring [J].Talanta, 2020, 208: 120450
