Clinical significance:
- Gefitinib’s strong inhibitory effect on CYP1A1 may provide
possibilities for its application in tumour prevention and reversal of
terminal tumour resistance.
- The long-term safety profile and efficacy of ningetinib combined with
gefitinib should be concerned in NSCLC patients.
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