Determination of GDC-0980 (apitolisib), a small molecule dual phosphatidylinositide 3-kinase/mammalian target of rapamycin inhibitor in dog plasma by LC-MS/MS to support a GLP toxicology study

Biomed Chromatogr. 2015 Aug;29(8):1274-9. doi: 10.1002/bmc.3417. Epub 2015 Feb 10.


An LC-MS/MS method for the determination of GDC-0980 (apitolisib) concentrations in dog plasma has been developed and validated for the first time to support pre-clinical drug development. Following protein precipitation with acetonitrile, the resulting samples were analyzed using reverse-phase chromatography on a Metasil AQ column. The mass analysis was performed on a triple quadruple mass spectrometer coupled with an electrospray interface in positive ionization mode. The selected reaction monitoring transitions monitored were m/z 499.3 → 341.1 for GDC-0980 and m/z 507.3 → 341.1 for IS. The method was validated over the calibration curve range 0.250-250 ng/mL with linear regression and 1/x(2) weighting. Relative standard deviation (RSD) ranged from 0.0 to 10.9% and accuracy ranged from 93.4 to 113.6% of nominal. Stable-labeled internal standard GDC-0980-d8 was used to minimize matrix effects. This assay was used for the measurement of GDC-0980 dog plasma concentrations to determine toxicokinetic parameters after oral administration of GDC-0980 (0.03, 0.1 and 0.3 mg/kg) to beagle dogs in a GLP toxicology study. Peak concentration ranged from 3.23 to 84.9 ng/mL. GDC-0980 was rapidly absorbed with a mean time to peak concentration ranging from 1.3 to 2.4 h. Mean area under the concentration-time curve from 0 to 24 hours ranged from 54.4 to 542 ng h/mL.

Keywords: GDC-0980 (apitolisib); Good Laboratory Practice (GLP); LC-MS/MS; dual phosphatidylinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor; selected reaction monitoring.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Administration, Oral
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • Bridged Bicyclo Compounds, Heterocyclic / blood*
  • Dogs / blood*
  • Female
  • Male
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyrimidines / administration & dosage
  • Pyrimidines / blood*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Tandem Mass Spectrometry / methods
  • Toxicokinetics


  • 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
  • Bridged Bicyclo Compounds, Heterocyclic
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines
  • TOR Serine-Threonine Kinases