神经母细胞瘤患儿中伊立替康及其3种代谢物的治疗药物监测

Therapeutic drug monitoring of irinotecan and its three metabolites in children with neuroblastoma

关键词:  神经母细胞瘤  儿童  伊立替康  治疗药物监测

Key words:  neuroblastoma  children  irinotecan  therapeutic drug monitoring

摘要:

摘要：目的 建立一种液相色谱串联质谱法同时测定人血清中伊立替康(IRI)及3种代谢物(SN-38、SN-38G和APC)的浓度，并将此方法应用于神经母细胞瘤(NB)患儿的治疗药物监测(TDM)。方法 均以氘代同位素为内标，EC-C18 (2.1×50 mm, 2.7 μm) 色谱柱分离，水(含0.1%甲酸)和乙腈为流动相进行梯度洗脱，流速0.3 mL·min-1，以电喷雾电离以多反应监测模式进行质谱分析。用本方法测定NB患儿血清中IRI及3种代谢物的浓度并分析IRI药动学参数与骨髓抑制毒性标志物百分比变化之间的关系。结果 通过验证，该方法符合《中国药典》(2020年版)中有关线性范围、定量下限、准确度、精密度、基质效应和稳定性的要求。相关分析结果显示，中性粒细胞百分比变化与AUCSN-38/AUCIRI (r=-0.700，P=0.036) 和AUCSN-38G/AUCSN-38 (r=0.700，P=0.036) 相关；淋巴细胞(r=-0.915，P=0.001)和血小板(r=-0.878，P=0.002)百分比变化均与AUCAPC/AUCIRI相关。结论 该方法快速、灵敏、准确度高，适用于临床实施IRI及其代谢物的TDM。NB患儿体内IRI代谢与骨髓抑制毒性之间具有一定的相关性，尚有待更大样本量的研究。

Abstract:

ABSTRACT: OBJECTIVE To establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of irinotecan (IRI) and three metabolites (SN-38, SN-38G and APC) concentrations in human serum, and to apply this method to therapeutic drug monitoring (TDM) in children with neuroblastoma (NB). METHODS The analytes were separated on an EC-C18 (2.1×50 mm, 2.7 μm) chromatographic column using deuterated isotopes as internal standards, with water (containing 0.1% formic acid) and acetonitrile as mobile phases in a gradient elution at a flow rate of 0.3 mL·min-1. The detection was performed with multiple reaction monitoring mode coupled with electrospray ionization source. Serum concentrations of IRI and its three metabolites were determined by this method and the relationships between IRI pharmacokinetic parameters and percentage changes in markers of myelosuppressive toxicity were analyzed. RESULTS The method was validated to meet the requirements of the Chinese Pharmacopoeia (2020 edition) regarding linearity, lower limit of quantification, accuracy, precision, matrix effect and stability. Correlation analysis showed that the percentage changes of neutrophil count were correlated with AUCSN-38/AUCIRI (r=-0.700, P=0.036) and AUCSN-38G/AUCSN-38 (r=0.700, P=0.036); the percentage changes of lymphocyte count (r=-0.915, P=0.001) and platelets (r=-0.878, P=0.002) were associated with AUCAPC/AUCIRI. CONCLUSION The method is rapid, sensitive, accurate and suitable for clinical implementation of TDM of IRI and its metabolites. There is a correlation between IRI metabolism and myelosuppressive toxicity in children with NB, which is yet to be investigated with a larger sample size.