Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of GDC-0879 and its metabolite in dog plasma using solid phase extraction.
A liquid-chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of GDC-0879 and its ketone metabolite (M1) in dog plasma to support preclinical toxicokinetic evaluation. The method consisted of solid phase extraction for sample preparation and LC-MS/MS analysis in positive ion mode using electrospray ionization for analysis. D(4)-GDC-0879 and (13)C(2)-D(2)-M1 were used as internal standards. A quadratic regression (weighted 1/concentration(2)) was used to fit calibration curves over the concentration range of 1-1000 ng/ml for both GDC-0879 and M1. The accuracy (%bias) at the lower limit of quantitation (LLOQ) was 12.0% and 2.0% for GDC-0879 and M1, respectively. The precision (%CV) for samples at the LLOQ was 11.3% and 2.6% for GDC-0879 and M1, respectively. For quality control samples at 3.00, 400 and 800 ng/ml, the between run %CV was ≤3.9% for GDC-0879 and ≤2.4% for M1. Between run %bias ranged from 4.6 to 12.0% for GDC-0879 and from -0.8 to 2.7% for M1. GDC-0879 and M1 were stable in dog plasma for at least 44 days at -70 °C.
Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, USA.
Bilin
B
Chou
Ryan S
RS
Adler
Min
M
Meng
Shaundel
S
Percey
Brian
B
Dean
Cornelis E C A
CE
Hop
Young G
YG
Shin
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000633:toxicity; D001711:Biotransformation; D002138:Calibration; D002853:Chromatography, Liquid / Q000592:standards; D004285:Dogs; D004355:Drug Stability; D005260:Female; D007192:Indenes / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000633:toxicity; D007262:Infusions, Intravenous; D007659:Ketones / Q000097:blood; D057230:Limit of Detection; D008297:Male; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000633:toxicity; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000633:toxicity; D012015:Reference Standards; D012044:Regression Analysis; D015203:Reproducibility of Results; D052616:Solid Phase Extraction / Q000592:standards; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry / Q000592:standards; D048490:raf Kinases / Q000037:antagonists & inhibitors
C540167:2-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol; D000970:Antineoplastic Agents; D007192:Indenes; D007659:Ketones; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D048490:raf Kinases