Xiao Ding
Department of Drug Metabolism and Pharmacokinetics in Genentech, USA
Title: Quantitation of 14C-GDC-0032 (14C-taselisib) in human plasma by UPLC-accelerator mass spectrometry for the determination of absolute bioavailability of GDC-0032 in human
Biography
Biography: Xiao Ding
Abstract
GDC-0032 (taselisib) is a potent, selective small-molecule inhibitor of Class I phosphoinositide 3-kinase (PI3K). It is being developed by Genentech for the treatment of various malignancies and is currently in multiple clinical trials. An accelerator mass spectrometry (AMS) method for the determination of 14C-GDC-0032 concentrations in human plasma was developed and qualified for the first time according to the Guidance for Industry: Bioanalytical Method Validation issued by the Food and Drug Administration (FDA). The absolute bioavailability of GDC-0032 was determined following oral administration of 3-mg GDC-0032 and IV administration of 3-μg/200 nCi 14C-GDC-0032 in male healthy volunteers in a clinical trial. UPLC-AMS method provided high selectivity and high sensitivity due to its nature of measuring the absolute 14C label. The method was qualified over the calibration curve range 0.168 to 100.8 pg/mL (0.025 to 15.0 dpm/mL) using linear regression and 1/y² weighting. Within-run relative standard deviation (%RSD) ranged from 1.87 to 8.59%, while the between-run %RSD varied from 3.21 to 7.29% for QCs using a standard curve model. The accuracy ranged from 98.60% to 109.93% of nominal for within-run and 100.96% to 106.95% of nominal for between-run at all concentrations. Extraction recovery factor of 14C-GDC-0032 was 0.9050. Stability of 14C-GDC-0032 was established in human plasma for 51 days at -70 ï‚°C and established in reconstituted sample extracts for 20 hours at -70 ï‚°C. The absolute bioavailability of GDC-0032 capsules was 57.4% (34.6% - 80.3%).