Indexed on: 28 May '19Published on: 29 Mar '19Published in: Journal of Pharmaceutical and Biomedical Analysis
Irinotecan hydrochloride liposome injection (IHLI) is a formulation of anticancer drug irinotecan hydrochloride (CPT-11) entrapped in the aqueous core of liposomes. To understand the pharmacokinetic property and evaluate the relationship between pharmacokinetics and pharmacodynamics/toxicity of IHLI, it is of prime importance to determine the concentrations of free CPT-11, total CPT-11 and its main metabolites (SN-38 and SN-38 G) in human plasma. In this paper, we developed and validated a sensitive and reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to quantify the concentrations of these related substances in human plasma. Free CPT-11, SN-38 and SN-38 G in human plasma were simultaneously separated and extracted by 96-well solid phase extraction (SPE) plate, while total CPT-11 was extracted by protein precipitation (PP) method. The analytes were chromatographed on an Acquity UPLC BEH C column and then detected on a Xevo TQ-S tandem mass spectrometer in multiple reactions monitoring (MRM) mode using positive electrospray ionization (ESI). The UPLC-MS/MS method combined with SPE and PP techniques were fully validated in line with existing guidelines issued by regulatory agencies. In brief, all the analytes achieved a satisfactory selectivity and sensitivity in this method. The calibration curves were proved to be linear over the concentration range of 10-10000 ng/mL for total CPT-11, 0.5-1000 ng/mL for free CPT-11, 0.5-200 ng/mL for SN-38 and SN-38 G, respectively. For all the analytes, the intra- and inter-run precisions were less than 11.4% and the accuracies (in terms of RE%) were within -7.7-7.3% except for accuracies of LLOQs were within -15.8 to 7.2%. Besides, carry-over, extraction recovery, matrix effect, dilution integrity, stability and special matrices were also assessed. Finally, the method was successfully applied to a phase I clinical pharmacokinetic study of IHLI in Chinese subjects with advanced solid tumors. Copyright © 2019. Published by Elsevier B.V.