Development and validation of LC-MS/MS method for tomivosertib quantification in plasma: insights into pharmacokinetics and metabolic stability

초록

A rapid, selective, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for quantifying tomivosertib (eFT508) in plasma from preclinical animals (rat and mouse). Tomivosertib was quantified using LC-MS/MS assay involving simple protein precipitation, followed by chromatographic separation on a Synergi Polar-RP 80 & Aring; column. Gradient elution was performed using 0.1% formic acid in distilled water and acetonitrile at a 0.3 mL/min flow rate. Multiple reaction monitoring (MRM) transitions were set at m/z 341.2 -> 216.0 for tomivosertib and m/z 249.0 -> 233.0 for the internal standard (IS), pyrimethamine, in positive ionization mode. Linearity (1-2000 ng/mL), accuracy, precision, carryover, matrix effects, recovery, extraction efficiency, and stability evaluated the performance of the developed method. Systemic and oral pharmacokinetics were evaluated in mice. The assay demonstrated adequate linearity, accuracy, precision, and no significant matrix effects, with consistent recovery and extraction efficiency. Tomivosertib was stable in the plasma and hepatic microsomal fractions of the studied species. Pharmacokinetic analysis in mice revealed moderate clearance (CL = 50.29 mL/min/kg), large volume distribution (Vss = 6506 mL/kg), and bioavailability ranging from 55.66-82.50%, with a greater than dose-proportional increase in exposure at a dose of 10 mg/kg. The findings of this study demonstrate that the developed method could be valuable for future research and development of tomivosertib.

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