title: 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.
abstract: 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.
authors: Genentech, Drug Metabolism and Pharmacokinetics, MS 41-2A, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors: Xiao
authors: X
authors: Ding
authors: Genentech, Drug Metabolism and Pharmacokinetics, MS 41-2A, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors: Laurent
authors: L
authors: Salphati
authors: Genentech, Safety Assessment, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors: Amy
authors: A
authors: Kim
authors: Genentech, Safety Assessment, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors: Eric
authors: E
authors: Morinello
authors: Genentech, Safety Assessment, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors: Lisa
authors: L
authors: Wong
authors: Genentech, Drug Metabolism and Pharmacokinetics, MS 41-2A, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors: Jodie
authors: J
authors: Pang
authors: Tandem Labs, 1121 East 3900 South, Salt Lake City, UT, 84124, USA.
authors: Shaundel
authors: S
authors: Percey
authors: Tandem Labs, 1121 East 3900 South, Salt Lake City, UT, 84124, USA.
authors: Min
authors: M
authors: Meng
authors: Tandem Labs, 1121 East 3900 South, Salt Lake City, UT, 84124, USA.
authors: Scott
authors: S
authors: Reuschel
authors: Genentech, Drug Metabolism and Pharmacokinetics, MS 41-2A, 1 DNA Way, South San Francisco, CA, 94080, USA.
authors: Brian
authors: B
authors: Dean
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood*; D004285:Dogs / Q000097:blood*; D005260:Female; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry / Q000379:methods; D066007:Toxicokinetics
chemical_list: C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases
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