Yan Li1, Paul H Severin2, Mark R Hoffmann2, Dennis L Miller2, Scott A Monk3, Alan R Kugler4. 1. Early Clinical Development, IMED Biotech Unit, AstraZeneca, Waltham, MA, USA 02451. 2. Clinical Laboratories, Covance Laboratories, Inc., Madison, WI, USA 53704. 3. Drug Disposition, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN, USA 46285. 4. Clinical Pharmacology, Coastal Pharma Group, Concord, MA, USA 01742.
Abstract
AIM: AZD3293 is a novel BACE1 inhibitor in Phase III development for Alzheimer's disease. Sensitive and robust bioanalytical methods were required to quantitate AZD3293 and its metabolite AZ13569724 in human biological matrices. METHODOLOGY/ RESULTS: Human plasma was prepared by protein precipitation. Linearity for both analytes was in the range of 0.5-500 ng/ml with up to 100-fold dilution. Plasma ultrafiltrate samples were prepared using Centrifree® ultrafiltration device. Urine and CSF samples were analyzed directly after dilution. A 27% decrease in AZD3293 concentrations in the CSF collection apparati was found due to nonspecific binding. Incurred sample reanalysis was acceptable. CONCLUSION: Methods for simultaneous quantitation of AZD3293 and its metabolite AZ13569724 in human biological matrices have been validated and successfully applied to clinical studies.
AIM: AZD3293 is a novel BACE1 inhibitor in Phase III development for Alzheimer's disease. Sensitive and robust bioanalytical methods were required to quantitate AZD3293 and its metabolite AZ13569724 in human biological matrices. METHODOLOGY/ RESULTS:Human plasma was prepared by protein precipitation. Linearity for both analytes was in the range of 0.5-500 ng/ml with up to 100-fold dilution. Plasma ultrafiltrate samples were prepared using Centrifree® ultrafiltration device. Urine and CSF samples were analyzed directly after dilution. A 27% decrease in AZD3293 concentrations in the CSF collection apparati was found due to nonspecific binding. Incurred sample reanalysis was acceptable. CONCLUSION: Methods for simultaneous quantitation of AZD3293 and its metabolite AZ13569724 in human biological matrices have been validated and successfully applied to clinical studies.
Authors: Naidong Ye; Scott A Monk; Pankaj Daga; David M Bender; Laura B Rosen; Jamie Mullen; Margaret C Minkwitz; Alan R Kugler Journal: Clin Pharmacol Drug Dev Date: 2018-01-10