Development and validation of sensitive and selective LC-MS/MS methods for the determination of BMS-708163, a gamma-secretase inhibitor, in plasma and cerebrospinal fluid using deprotonated or formate adduct ions as precursor ions.
BMS-708163 is a gamma-secretase inhibitor that is being developed for the treatment of Alzheimer's disease. Several LC-MS/MS methods have been developed for the determination of BMS-708163 in both plasma and cerebrospinal fluid in support of dog, rat, mouse and human studies. To support non-clinical studies, an LC-MS/MS method with a lower limit of quantitation (LLOQ) of 5 ng/mL, was developed and validated in dog, rat, and mouse plasma by using the deprotonated ion as the precursor ion. To support clinical studies, an LC-MS/MS method with LLOQ of 0.1 ng/mL, was developed and validated in human plasma by using the formate adduct as the precursor ion. Formic acid (0.01%) in water and acetonitrile was found to be the most favorable mobile phases for both deprotonated and formate adduct ions in negative electrospray ionization mode. A combination of a 3M Empore C18 plate for SPE and a Waters Atlantis dC18 analytical column for separation was used to achieve a highly selective solid phase extraction and chromatographic procedure from plasma without dry down and reconstitution steps. In the development of an assay for BMS-708163 in cerebral spinal fluid (CSF), significant non-specific binding of BMS-708163 was observed and resolved with pre- or post-spike of 0.2% Tween 20 into CSF samples. A dilute-and-shoot LC-MS/MS method with LLOQ of 0.1 ng/mL was developed and validated to assess BMS-708163 exposure in human CSF.
Gu
Huidong
H
Bioanalytical Sciences, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08543, USA. huidong.gu@bms.com
Deng
Yuzhong
Y
Wang
Jian
J
Aubry
Anne-Françoise
AF
Arnold
Mark E
ME
D000097:Acetonitriles / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D004285:Dogs; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry; D005561:Formates / Q000737:chemistry; D006801:Humans; D051379:Mice; D010069:Oxadiazoles / Q000032:analysis* / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D051381:Rats; D012044:Regression Analysis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D052616:Solid Phase Extraction; D013449:Sulfonamides / Q000032:analysis* / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry; D053719:Tandem Mass Spectrometry / Q000379:methods*
D000097:Acetonitriles; C554092:BMS 708163; D004791:Enzyme Inhibitors; D005561:Formates; D010069:Oxadiazoles; D011136:Polysorbates; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; C032159:acetonitrile