Therapeutic Drug Monitoring of Irinotecan and Its Three Metabolites in Children with Neuroblastoma

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 mm×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 AUC_SN-38/AUC_IRI(r=−0.700, P=0.036) and AUC_SN-38G/AUC_SN-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 AUC_APC/AUC_IRI.

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.