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Drug interaction of ningetinib and gefitinib involving CYP1A1 and efflux transporters in non-small cell lung cancer patients
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  • Lu Liu,
  • Qian Wang,
  • Cen Xie,
  • Ning Xi,
  • Zitao Guo,
  • Ming Li,
  • Xiangyu Hou,
  • Ningjie Xie,
  • Jing Li,
  • Xiaoyan Chen
Lu Liu
Shanghai Institute of Materia Medica Chinese Academy of Sciences

Corresponding Author:[email protected]

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Qian Wang
Sunshine Lake Pharma Co Ltd
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Cen Xie
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
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Ning Xi
Sunshine Lake Pharma Co Ltd
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Zitao Guo
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
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Ming Li
Sunshine Lake Pharma Co Ltd
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Xiangyu Hou
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
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Ningjie Xie
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
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Jing Li
Sunshine Lake Pharma Co Ltd
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Xiaoyan Chen
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
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Abstract

Background and Purpose: Ningetinib is a tyrosine kinase inhibitor for the treatment of non-small cell lung cancer (NSCLC). When co-administered with gefitinib, the high plasma exposure of N-demethylated metabolite M1 was reduced by more than 80%, whereas it is surprising that of ningetinib was not clearly affected. The present study aims to investigate the drug interaction mechanism of ningetinib and gefitinib. Experimental Approach: NSCLC patients were recruited. Metabolic and transport mechanisms were investigated using in vitro models. Deuterated M1 (D6-M1) and mice were used to study the pharmacokinetic of M1. Key Results: In vitro experiments indicated that CYP1A1 was primarily responsible for M1 formation. Gefitinib was demonstrated to a strong inhibitor of CYP1A1 with Ki value of 0.095 μM. Co-administration of ningetinib increased blood exposure of intravenously administered D6-M1 by 75% in mice. M1 was identified as the substrate of the efflux transporters P-gp, BCRP and MRP2, while ningetinib was an inhibitor of these efflux transporters. Consequently, the high plasma exposure of M1 in patients was attributed to its low tissue affinity and the inhibitory effect of the parent drug on M1 canalicular efflux. Conclusion and Implications: When co-administered, gefitinib inhibited the formation of M1 and reduced its plasma exposure, but due to the low metabolic yield of M1 in vivo, the pharmacokinetics of the parent drug ningetinib was not influenced. Inhibition of the CYP1A1 may increase the target tissue concentration of ningetinib. The long-term safety profile and efficacy of ningetinib combined with gefitinib should be concerned in NSCLC patients.