Abstract
Naquotinib (ASP8273, NQT) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs). NQT was found to be more effective than osimertinib against the EGFR L858R plus T790M mutation (L858R+T790M). A rapid resolution liquid chromatography (RRLC)-tandem mass spectrometry (MS/MS) method was developed and validated for NQT quantification and its metabolic stability was investigated. NQT and foretinib (FTB) as an internal standard (IS) were separated using a mobile phase under isocratic conditions with a C18 column (reversed phase system). The linearity of the analytical method ranged from 5 to 500 ng mL−1 (coefficient of correlation [r2] ≥ 0.9999) in a human liver microsome (HLM) matrix. The limit of detection and limit of quantification were 0.78 and 2.36 ng mL−1, respectively. The inter-day and intra-day accuracy and precision were −6.36 to 1.88 and 0.99 to 2.58%, respectively. The metabolic stability of NQT in the HLM matrix was calculated using the in vitro half-life (t1/2, 67.96 min) and intrinsic clearance (Clint, 2.12 mL min−1 kg−1). NQT is considered to be a moderate extraction ratio drug that is moderately excreted from the human body compared with other related TKIs. This proposed methodology is thought to be the first method for assessing NQT concentration and its metabolic stability.
Highlights
The third-generation Tyrosine kinase inhibitors (TKIs) maintain the second-generation drugs' bene ts by preventing epidermal growth factor receptor (EGFR) mutations and surmounting the T790M resistance mutation.[13,14] Naquotinib (ASP8273, NQT) is considered a novel third-generation EGFRTKI and was found to be more effective than osimertinib against the L858R plus T790M mutation (L858R+T790M)
NQT could be considered a moderate extraction ratio drug and, is moderately excreted from the human body compared to other TKIs.[18,19,20,21]
67.96 min 2.12 mL minÀ1 kgÀ1 a X: ln of percentage of NQT remaining. b Linear part regression equation. c Correlation coefficient. d Half-life. e Intrinsic clearance. These results revealed that the metabolic stability of NQT was characterized by a very low Clint (2.12 mL minÀ1 kgÀ1) and very long in vitro t1/2 value (67.96 min) that revealed the moderate clearance of NQT from the blood by the liver and possible well-controlled in vivo bioavailability
Summary
The third-generation TKIs maintain the second-generation drugs' bene ts by preventing EGFR mutations and surmounting the T790M resistance mutation.[13,14] Naquotinib (ASP8273, NQT) is considered a novel third-generation EGFRTKI and was found to be more effective than osimertinib against the L858R plus T790M mutation (L858R+T790M). Naquotinib and osimertinib showed a wide therapeutic window and similar efficacy for EGFR exon 20 insertions cells.[16]. If the test drug is quickly metabolized, it will show a low in vivo bioavailability value.[17] NQT could be considered a moderate extraction ratio drug and, is moderately excreted from the human body compared to other TKIs.[18,19,20,21] This implies a lower risk of drug accumulation inside the body in comparison to other TKIs (e.g. dacomitinib). The metabolic stability of NQT was determined by computing two important parameters (intrinsic clearance and in vitro half-life [t1/2]) that could be utilized to further calculate
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