A fully validated method for simultaneous determination of icotinib, osimertinib, gefitinib and O-desmethyl gefitinib in human plasma using UPLC-MS/MS for therapeutic drug monitoring

Bo Li; Wenqian Chen; Fang Liu; Xiaoxue Wang; Wei Qin; Shu Li; Hongkai Lu; Guan Wang; Xiaoyang Liu; Pengmei Li; Xianbo Zuo; Xianglin Zhang; Lihong Liu; Meng Yang

doi:10.1016/j.jpba.2023.115697

A fully validated method for simultaneous determination of icotinib, osimertinib, gefitinib and O-desmethyl gefitinib in human plasma using UPLC-MS/MS for therapeutic drug monitoring

J Pharm Biomed Anal. 2023 Nov 30:236:115697. doi: 10.1016/j.jpba.2023.115697. Epub 2023 Sep 3.

Authors

Bo Li¹, Wenqian Chen¹, Fang Liu¹, Xiaoxue Wang¹, Wei Qin¹, Shu Li¹, Hongkai Lu², Guan Wang³, Xiaoyang Liu⁴, Pengmei Li¹, Xianbo Zuo¹, Xianglin Zhang¹, Lihong Liu⁵, Meng Yang⁶

Affiliations

¹ Department of Pharmacy, China-Japan Friendship Hospital, Beijing 100029, China.
² Department of Blood Transfusion, China-Japan Friendship Hospital, Beijing 100029, China.
³ Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
⁴ Department of Pharmacy, China-Japan Friendship Hospital, Beijing 100029, China; Department of Pharmacy Administration and Clinical Pharmacy School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
⁵ Department of Pharmacy, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address: hongllh@126.com.
⁶ National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address: yangm_zoe@163.com.

PMID: 37713984
DOI: 10.1016/j.jpba.2023.115697

Abstract

Background and aims: A few researches have reported the exposure-efficacy/toxicity relationships of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). On account of the large interpatient pharmacokinetic variability, therapeutic drug monitoring (TDM) seems promising for optimizing dosage regimen and improving treatment efficacy and safety. Therefore, a rapid and convenient ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of icotinib, osimertinib, gefitinib and O-demesthyl gefitinib in human plasma for TDM.

Materials and methods: Icotinib-D₄ and osimertinib-¹³CD₃ were used as the internal standards (ISs). The samples were prepared by protein precipitation using acetonitrile. Chromatographic separation was achieved on a 40 ℃ Shimadzu Shim-pack Scepter C18-120 column (2.1 ×50 mm, 3.0 µm, Japan) by a Shimadzu 30 A solvent management system. Detection was carried out using a Shimadzu LC-MS 8050CL triple quadrupole mass spectrometer coupled with an electrospray ionization source in positive mode.

Results: This analytical method was fully validated with selectivity, carry-over, linearity, lower limit of quantification, accuracy (from 92.68% to 106.62%) and precision (intra- and inter-day coefficients of variation ranged from 0.92% to 9.85%), matrix effect, extraction recovery, stability and dilution integrity. The calibration curves were developed to be within the concentration ranges of 200-4000 ng/mL for icotinib, 50-1000 ng/mL for osimertinib, gefitinib and O-desmethyl gefitinib in human plasma which meet the needs of routine TDM.

Conclusions: The proposed method was used in 100 patients with non-small cell lung cancer for monitoring plasma concentration of the mentioned EGFR-TKIs. The trough concentrations of ICO were distributed between 226.42 ng/mL and 3853.36 ng/mL, peak concentrations were between 609.20 ng/mL and 2191.54 ng/mL. The trough concentrations of OSI were distributed between 110.48 ng/mL and 1183.13 ng/mL. The trough concentrations of GEF were distributed between 117.71 ng/mL and 582.74 ng/mL, while DeGEF was distributed from 76.21 ng/mL to 1939.83 ng/mL with two less than 20 ng/mL. The results of therapeutic drug monitoring aimed to investigate exposure-efficacy/toxicity relationship and improve the efficacy and safety of targeted therapies.

Keywords: Gefitinib; Icotinib; O-demesthyl gefitinib; Osimertinib; Therapeutic drug monitoring; UPLC-MS/MS.