Abstract
Aim and Objective: An analytical method for the determination of mobocertinib, an investigational tyrosine kinase inhibitor, was developed and optimized by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) in rat plasma.
Materials and Methods: Plasma samples were pretreated by the protein precipitation method with a methanol solution of osimertinib as the internal standard (IS). Chromatographic separation was performed using an Inertsil ODS-3 column (50 mm × 4.6 mm, I.D. 5 μm) with the temperature maintained at 40°C. The mobile phase consisted of water (containing 0.1% formic acid) and methanol in a gradient mode at a flow rate of 0.5 mL/min. Mass spectrometric detection was carried out in the selected reaction monitoring (SRM) mode with positive electrospray ionization, and the mass transitions of mobocertinib and osimertinib were m/z 587.01 → 71.88 and m/z 499.80 → 71.94, respectively. The method was validated in terms of selectivity, linearity, accuracy and precision, extraction recovery and matrix effect, stability and carryover as per the guidelines for bioanalytical method validation (FDA, 2018). The method was applied to the pharmacokinetic study of mobocertinib in rats by oral gavage at the doses of 2, 6, and 18 mg/kg. A total of 216 plasma samples from 18 rats were analyzed. Results: The results showed good linearity over the range of 1-1000 ng/mL (R2 = 0.9957). The intra-batch accuracy was within 94.65-102.59% and the precision was within 5.49-10.46%. The inter-batch accuracy was within 97.08-102.25% with a precision of 7.54-10.13%. The extraction recovery and matrix factor were acceptable for the bioanalysis of mobocertinib. Additionally, mobocertinib was found to be stable under the detected conditions. Mobocertinib showed linear pharmacokinetic characteristics following oral administration to rats at 2.0-18.0 mg/kg. Conclusion: The developed and validated method was successfully employed in the pharmacokinetic study in rats following oral administration of mobocertinib at the doses of 2, 6, and 18 mg/kg.Keywords: Mobocertinib, epidermal growth factor, receptor tyrosine, kinase inhibitor, pharmacokinetics study, rat.
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