A contrast in safety, pharmacokinetics, and pharmacodynamics across age groups after a single 50-mg oral dose of the γ-secretase inhibitor avagacestat.

Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens R.
Journal   Br J Clin Pharmacol.
Species  
Analytes Measured   Abeta 40
Matrix Tested   Plasma
Year   2012
Volume  
Page Numbers  
Application   Alzheimers
Abstract
Aim: To evaluate the single-dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women.

Methods: All subjects received double-blinded administration of a single 50-mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-β (Aβ)(1-40) levels, and exploration of Notch biomarkers.

Results: Avagacestat 50-mg capsule was well-tolerated and rapidly absorbed among young and elderly subjects, with a median T(max) between 1 and 2 hours post-dose and an average half-life between 41 and 71 hours. In general, subjects aged 75 years or more had higher AUC(inf) values than those aged less than 75 years. An exploratory analysis of Aβ(1-40) serum levels showed a pattern of decreasing levels over the first 4-6 hours followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose-limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly.

Conclusions: The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer's disease.

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