title: Validation and determination of taselisib, a β-sparing phosphoinositide 3-kinase (PI3K) inhibitor, in human plasma by LC-MS/MS.
abstract: A liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for the determination of taselisib (GDC-0032, RO5537381) concentrations in human plasma has been developed and validated to support bioanalysis of clinical samples. Solid phase extraction (SPE) was used to extract plasma samples (50μL) and the resulting samples were analyzed using reversed phase chromatography and mass spectrometry coupled with an atmospheric pressure chemical ionization interface. The mass analysis of taselisib was performed using multiple reaction monitoring transitions in positive ionization mode. The method was validated over the calibration curve range 0.400-400ng/mL using linear regression and 1/x(2) weighting. The within-run relative standard deviation (%RSD) ranged from 1.3 to 5.6%, while the between-run %RSD varied from 2.0 to 4.5% for LLOQ, low, medium, medium high and high QCs. The accuracy ranged from 94.7 to 100.3% of nominal for within-run and 96.0-99.0% of nominal for between-run for the same QCs. Extraction recovery of taselisib was between 83.8% and 92.9%. Stability of taselisib was established in human plasma for 977days at -20°C and -70°C and established in sample extracts for 96h when stored at 2 - 8°C. Stable-labeled internal standard was used to minimize matrix effects. Mean single dose pharmacokinetic parameters determined using this method for a phase I/II clinical trial were: Cmax=35.2ng/mL, AUC0-inf=1570ngh/mL, and T1/2=39.3h.
authors.affiliation: Genentech, Drug Metabolism and Pharmacokinetics, 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: ding.xiao@gene.com.
authors.forename: X
authors.initials: X
authors.lastname: Ding
authors.affiliation: Genentech, Clinical Pharmacology, 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: K
authors.initials: K
authors.lastname: Faber
authors.affiliation: Covance Laboratories, 3301 Kinsman Blvd., Madison, WI 53704, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
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: D
authors.initials: D
authors.lastname: Dorshorst
authors.affiliation: Genentech, 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: D000970:Antineoplastic Agents / Q000032:analysis / Q000097:blood*; D019540:Area Under Curve; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods*; D056148:Chromatography, Reverse-Phase / Q000379:methods; D004355:Drug Stability; D004356:Drug Storage; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000032:analysis / Q000097:blood*; D016014:Linear Models; D010077:Oxazepines / Q000032:analysis / Q000097:blood*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015203:Reproducibility of Results; D052616:Solid Phase Extraction / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods*; D013696:Temperature; D013997:Time Factors
chemical_list: C582924:2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide; D000970:Antineoplastic Agents; D007093:Imidazoles; D010077:Oxazepines; D000081082:Phosphoinositide-3 Kinase Inhibitors
keywords: Human plasma; LC–MS/MS; Solid phase extraction (SPE); Taselisib (GDC-0032, RO5537381); β-Sparing phosphoinositide 3-kinase (PI3K) inhibitor