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Drug interaction of ningetinib and gefitinib involving CYP1A1 and efflux transporters in non‐small cell lung cancer patients
Author(s) -
Liu Lu,
Wang Qian,
Xie Cen,
Xi Ning,
Guo Zitao,
Li Ming,
Hou Xiangyu,
Xie Ningjie,
Sun Mingming,
Li Jing,
Chen Xiaoyan
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14621
Subject(s) - gefitinib , pharmacology , in vivo , efflux , lung cancer , tyrosine kinase inhibitor , pharmacokinetics , drug , chemistry , drug interaction , medicine , cancer , epidermal growth factor receptor , biology , biochemistry , microbiology and biotechnology
Aims Ningetinib is a tyrosine kinase inhibitor for the treatment of non‐small cell lung cancer (NSCLC). The present study aims to investigate the drug interaction of ningetinib and gefitinib and the mechanism of high plasma exposure of N ‐demethylated ningetinib (M1) in NSCLC patients. Methods Patients with NSCLC were recruited. Metabolism and transport assays were performed using in vitro models. Deuterated M1 was used to study the effects of ningetinib and gefitinib on M1 efflux in Institute of Cancer Research (ICR) mice. Results Upon co‐administration of ningetinib with gefitinib, the plasma exposure of M1 was reduced by 80%, whereas that of ningetinib was not affected. In vitro experiments indicated that CYP1A1 was primarily responsible for M1 formation. Gefitinib was demonstrated to be a strong inhibitor of CYP1A1 with K i value of 0.095 μM. M1 was identified as a substrate of efflux transporters P‐gp and BCRP, while ningetinib and gefitinib were demonstrated to be their inhibitors, which was consistent with the results in mice. However, the inhibitory effect of gefitinib on efflux in vivo was negligible in the presence of ningetinib. Conclusion The high plasma exposure of M1 in patients was attributed to the inhibition of M1 efflux by ningetinib and its low tissue affinity. When co‐administered, gefitinib inhibited the formation of M1, but due to the low metabolic yield of M1 in vivo, the pharmacokinetics of ningetinib was not influenced. Inhibition of CYP1A1 may increase the concentration of ningetinib in target tissues, and the long‐term safety and efficacy of ningetinib combined with gefitinib should be evaluated.