Development and validation of an LC–MS/MS method for the determination of BLU-945, a fourth-generation EGFR tyrosine kinase inhibitor, in rat and mouse plasma: application to a pharmacokinetic study in rats

Abstract

Abstract BLU-945, a new-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a potential drug candidate for the treatment of non-small-cell lung cancer (NSCLC) in patients with mutations that are resistant to previous generations of EGFR TKI. This compound has been investigated in preclinical and phase 1 dose-escalation studies that require a bioanalytical method for drug quantitation. In this study, an LC–MS/MS method was developed and validated for the quantitation of BLU-945 in rodent plasma and was applied to pharmacokinetic studies. The compound was extracted from plasma samples using a simple protein precipitation method. The method was validated in the linearity range of 1–1000 ng/mL with acceptable accuracy and precision, no matrix effects, and complete extraction recovery. BLU-945 was stable in the plasma quality control samples under various handling and storage conditions. The compound was stable after 4-h incubation in human, mouse, and rat plasma but was extensively metabolized in the microsomal fractions of these species. Furthermore, the validated analytical method was applied to a pharmacokinetic study in rats, revealing that BLU-945 had a high oral bioavailability range (55.91–105.6%) with a nonlinear pharmacokinetic profile up to an oral dose of 20 mg/kg. The validated bioanalytical method and findings of our study represent valuable assets for future investigations and clinical studies of BLU-945.

Keywords

• Tyrosine kinase inhibitor
• BLU-945
• LC–MS/MS
• Validation
• Pharmacokinetics