Abstract
Dacomitinib (DMB) is a second-generation irreversible tyrosine kinase inhibitor (TKI) that is claimed to overcome the disadvantages of the resistance reported for first-line epidermal growth factor receptor (EGFR) TKIs. Towards the end of 2018, the US Food and Drug Administration approved DMB in the form of VIZIMPRO tablets. In the current study, a validated LC-MS/MS assay was established for DMB quantification in rat liver microsomes (RLMs) with application to the drug metabolic stability assessment. Chromatographic resolution of DMB and lapatinib (internal standard) was achieved using an isocratic mobile phase and a reversed-phase C18 column. The linearity of the established LC-MS/MS assay ranged from 2 to 500 ng/mL with r2 ≥ 0.9999. The limit of detection (LOD) and limit of quantification (LOQ) were 0.35 and 1.1 ng/mL, respectively. The precision and accuracy (both intra-day and inter-day) were 0.84–3.58% and 92.2–100.32%, respectively. The metabolic stability of DMB in the RLM matrix was estimated by calculating two parameters, in vitro t1/2 (0.97 mL/min/kg) and intrinsic clearance (157.5 min). Such values infer that DMB would be excreted very slowly from the human body, which might lead to possible bioaccumulation. To the best of our knowledge, this is the first method for DMB analysis in RLMs with metabolic stability estimation.
Highlights
Lung cancer is the leading cause of death among all cancer types, in particular, non-small cell lung cancer (NSCLC) is considered the most widespread [1,2,3,4,5], with an incidence of approximately 90%
Tyrosine kinase inhibitors (TKIs) that control epidermal growth factor receptor (EGFR) are very efficient in the treatment of cancers possessing EGFR mutations, with a characteristic therapeutic window
The established LC-MS/MS assay was validated for sensitivity, assay recovery, linearity, reproducibility, specificity, limit of quantification (LOQ), limit of detection (LOD). and stability according to the US Food and Drug Administration (FDA) guidelines [23]
Summary
Lung cancer is the leading cause of death among all cancer types, in particular, non-small cell lung cancer (NSCLC) is considered the most widespread [1,2,3,4,5], with an incidence of approximately 90%. The epidermal growth factor receptor (EGFR) signaling pathway has gained importance in the last few years as a therapeutic target for NSCLC [6]. Tyrosine kinase inhibitors (TKIs) that control EGFR are very efficient in the treatment of cancers possessing EGFR mutations, with a characteristic therapeutic window. First-line TKIs controlling EGFR (e.g., erlotinib and gefitinib) have good initial responses against these mutations [7, 8].
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