Development and validation of a new LC–MS/MS method for the determination of mefatinib in human plasma and its first application in pharmacokinetic studies

Abstract

Abstract Mefatinib (MET306) is a novel second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) designed to address the highly unmet clinical need of gefitinib-induced resistance and irreversibly bind to mutated tyrosine kinase domain of EGFR and human epidermal growth factor receptor 2 (HER2). In this study, a liquid chromatography–tandem mass spectrometry method was established and validated for determining MET306 in non-small cell lung cancer patients and a backpropagation artificial neural network was developed and constructed to predict the pharmacokinetic process. The mobile phase was water containing 5 mM ammonium acetate and acetonitrile at a flow rate of 0.3 mL min−1, within a 4.5 min run time. MET306 was separated on a Hypersil Gold-C18 at 40 °C and subjected to mass analysis using positive electrospray ionization. A total of 524 data were used as development groups and 145 data were used as testing groups. The final established Northern Goshawk Optimization-Backpropagation Artificial Neural Network (NGO-BPANN) model consisted of one input layer with 6 neurons, 1 hidden layer with 10 nodes, and 1 output layer with one node processed by MATLAB2021a.The calibration range of MET306 was 0.5–200 ng mL−1 with the correlation coefficient r ≥ 0.99. Accuracies ranged from 97.20 to 110.80% and the inter- and intra-assay precision were less than 15%. The ranges of extraction recoveries were 104.95% to 112.09% for analyte and internal standard and there was no significant matrix effect. The storage stability under different conditions was in accordance with the bioanalytical guidelines. The time-concentration profiles of the measured and predicted concentrations of MET306 by NGO-BPANN agree well. An NGO-BPANN model was developed to predict the plasma concentration and pharmacokinetic parameters of MET306 in the first time.

Keywords

• MET306
• LC–MS/MS
• First in human
• PK study
• NGO-BPANN