Clinical significance:
Introduction
Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer, and the majority of NSCLC patients present with symptoms in a late advanced stage (Malapelle, Muscarella, Pisapia, & Rossi, 2020). Currently treatment strategies for NSCLC have evolved to emphasize molecular targeted therapy based on the genomic classification of patients. And the therapeutic targets for NSCLC include epidermal growth factor receptor (EGFR), mechanistic target of rapamycin (mTOR), epidermal growth factor receptor 2 (ErbB2), phosphatidylinositol 3-kinase (PI3Ks), kirsten human rat sarcoma protein (KRAS), vascular epidermal growth factor receptor (VEGFR), anaplastic lymphoma kinase (ALK), mesenchymal-epithelial transition factor (c-MET), v-Raf murine sarcoma viral oncogene homolog B (BRAF), etc (Ai et al., 2018). The occurrence and development of tumours often involve the interaction of multiple receptors and signaling pathways, which makes it difficult to achieve satisfactory effect using single-targeted drugs (Zheng et al., 2017). In recent years, combination drug therapy has gradually become the focus of cancer treatment to improve the efficacy and overcome drug resistance such as the combination use of apatinib with icotinib (Xia et al., 2018), dovitinib with erlotinib (Das et al., 2015) for the treatment of NSCLC. However, the use of polypharmacotherapy makes drug-drug interactions due to inhibition or induction of drug-metabolizing enzymes and/or transporters virtually unavoidable, which may cause serious adverse events and even lead to the early termination of development or withdrawal of drugs from the market, such as terfenadine, astemizole, cisapride, and mibefradil (Alfaro, 2001). .
Ningetinib tosylate (CT-053PTSA, N-(3-fluoro-4-((7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide,Fig 1A) is a potent, orally bioavailable small molecule tyrosine kinase inhibitor (TKI) against c-MET, VEGFR as well as AXL, Mer, and FMS-like tyrosine kinase 3 (FLT3) in relation to tumour pathogenesis. It‘s now undergoing phase I/Ⅱ clinical study for NSCLC treatment (Wang. & Jin, 2018; Xi, Zhang, Wang, Wu, & Wang, 2014). In humans, N -demethylated ningetinib (M1, Fig 1B) was identified as the primary circulating metabolite, whose plasma exposure was about 1.7-fold that of the parent drug. Although M1 had almost no inhibitory effect on the antitumour targets antagonised by ningetinib, it should cause our concern in clinical studies of ningetinib because of its high plasma exposure.
Gefitinib is the first EGFR-targeting agent launched as an anti-cancer drug in Japan, Australia and the United Sates for the treatment of chemoresistant NSCLC (Rahman, Korashy, & Kassem, 2014; Ranson & Wardell, 2004) and was approved for the first-line treatment for metastatic NSCLC and granted orphan drug qualification by FDA (Kazandjian et al., 2016). However, resistance to EGFR-TKIs is inevitable due to various mechanisms, such as the secondary mutation (T790M), activation of alternative pathways (c-MET, HGF, AXL) and aberrance of the downstream pathway (K-RAS mutations, loss of PTEN), etc (Huang & Fu, 2015). Therefore, it would be reasonable to explore the feasibility and tolerability of combining EGFR-TKIs with multi-target TKIs in the treatment of NSCLC, such as co-administration of gefitinib with ningetinib.
To examine the effect of concomitant medication use on the clinical efficacy and safety, the potential pharmacokinetic interaction of therapeutic doses of gefitinib (250 mg) and ningetinib (60 mg) was firstly evaluated in patients with NSCLC. When co-administered with gefitinib, the plasma exposure of the primary circulating component M1 on the first and 28th days was reduced by more than 80%, suggestive of a drug-drug interaction between ningetinib and gefitinib. Nevertheless, it is interesting to note that the pharmacokinetics of ningetinib was almost unaffected. Several studies have shown gefitinib inhibited CYP2C19, CYP2D6, CYP2C9, CYP3A4, CYP1A2 and CYP2C8 activities to varying degrees (Filppula, Neuvonen, & Backman, 2014; Rahman et al., 2014). In addition, gefitinib was also an inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) (Galetti et al., 2015a; Kitazaki et al., 2005). To date, it was unknown whether inhibition of these metabolizing enzymes and transporters by gefitinib affected the pharmacokinetics of M1. Besides, it was puzzling that the plasma concentration of the parent drug has hardly changed when that of M1 with a high plasma exposure was dramatically reduced.
Hence, the purpose of the present study was to investigate the mechanism of M1 formation and the effect of gefitinib on M1 production, and further explore the reasons for the different effects on ningetinib and M1 by gefitinib using a variety of in vitro and in vivometabolic and transport models.
Materials and Methods