title: A supported liquid extraction-LC-MS/MS method for determination of GDC-0980 (Apitolisib), a dual small-molecule inhibitor of class 1A phosphoinositide 3-kinase and mammalian target of rapamycin, in human plasma.
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.
authors.affiliation: Genentech, Drug Metabolism and Pharmacokinetics, 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: dingx2@gene.com.
authors.forename: X
authors.initials: X
authors.lastname: Ding
authors.affiliation: Covance Laboratories, 3301 Kinsman Blvd., Madison, WI 53704, United States.
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.affiliation: Covance Laboratories, 3301 Kinsman Blvd., Madison, WI 53704, United States.
authors.forename: J
authors.initials: J
authors.lastname: McKnight
authors.affiliation: Covance Laboratories, 3301 Kinsman Blvd., Madison, WI 53704, United States.
authors.forename: C
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Covance Laboratories, 3301 Kinsman Blvd., Madison, WI 53704, United States.
authors.forename: K
authors.initials: K
authors.lastname: Strooisma
authors.affiliation: Genentech, Companion Diagnostics Development, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: H
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Genentech, Small Molecule Clinical Pharmacology, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: K
authors.initials: K
authors.lastname: Faber
authors.affiliation: Genentech, Small Molecule Clinical Pharmacology, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: J A
authors.initials: JA
authors.lastname: Ware
authors.affiliation: Genentech, Drug Metabolism and Pharmacokinetics, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: B
authors.initials: B
authors.lastname: Dean
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D002138:Calibration; D056148:Chromatography, Reverse-Phase / Q000592:standards; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage; D057230:Limit of Detection; D016014:Linear Models; D008875:Middle Aged; D058539:Phosphatidylinositol 3-Kinase / Q000008:administration & dosage / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D012015:Reference Standards; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000592:standards; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000592:standards; D055815:Young Adult
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; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases; D007654:Ketoconazole
keywords: Dual inhibitor of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR); GDC-0980 (Apitolisib); Human plasma; LC–MS/MS; Solid supported liquid extraction