ABSTRACT
A liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for the determination of GDC-0980 (Apitolisib) concentrations in human plasma has been developed and validated to support clinical development. Supported liquid extraction (SLE) was used to extract plasma samples (80µL) and the resulting samples were analyzed using reverse-phase chromatography and mass spectrometry coupled with a turbo-ionspray interface. The mass analysis of GDC-0980 was performed using multiple reaction monitoring (MRM) transitions in positive ionization mode. The method was validated over the calibration curve range 0.0500-25.0ng/mL using linear regression and 1/x(2) weighting. Within-run relative standard deviation (%RSD) ranged from 0.4 to 3.9%, while the between-run %RSD varied from 1.1 to 1.5% for QCs. The accuracy ranged from 96.1% to 106.7% of nominal for within-run and 96.7-106.7% of nominal for between-run at all concentrations including the LLOQ quality control at 0.0500ng/mL. Extraction recovery of GDC-0980 was between 72.4% and 75.5%. Stability of GDC-0980 was established in human plasma for 547 days at -20°C and -70°C and established in reconstituted sample extracts for 146h when stored at 2-8°C. Stable-labeled internal standard was used to minimize matrix effects. Mean pharmacokinetic parameters determined using this method for the day 1 control group in a phase I trial were: Cmax=11.1ng/mL, AUC0-inf=108ngh/mL, and T1/2=13.1h.
