The ?-Secretase Modulator, BMS-932481, Modulates A? Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers.
Ontology highlight
ABSTRACT: The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a ?-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) A?39, A?40, and A?42 while increasing A?37 and A?38, thereby providing evidence of ?-secretase enzyme modulation rather than inhibition. In plasma, reductions in A?40 and A?42 were observed with no change in total A?; in CSF, modest decreases in total A? were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70% CSF A?42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of A? lowering in Alzheimer's disease, this study demonstrates that ?-secretase modulation is achievable in healthy human volunteers and supports further efforts to discover well tolerated GSMs for testing in Alzheimer's disease and other indications.
SUBMITTER: Soares HD
PROVIDER: S-EPMC4931877 | biostudies-other | 2016 Jul
REPOSITORIES: biostudies-other
ACCESS DATA