Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers

Eric Siemers, Michael Skinner, Robert A. Dean, Celedon Gonzales, Julie Satterwhite, Martin Farlow, Daniel Ness, Patrick C. May

Research output: Contribution to journalArticle

219 Scopus citations


Amyloid β(Aβ) may play a central role in the pathogenesis of Alzheimer disease. A functional γ-secretase inhibitor, LY450139, was developed that inhibits Aβ formation in whole cell assays, transgenic mice, and beagle dogs. The authors wished to determine the safety and tolerability of this drug, and the reduction of Aβ in plasma and cerebrospinal fluid (CSF) after multiple doses. Volunteer subjects (N = 37) were studied using doses from 5 to 50 mg/ day given for 14 days. Plasma and CSF concentrations of LY450139, Aβ1-40 and Aβ1-x ("Aβ total") were determined, and safety and tolerability were assessed. The plasma half-life of LY450139 was approximately 2.5 hours. Pharmacokinetic analyses showed a linear relationship between dose and plasma concentrations, with a Cmax of 828 ± 19.2 ng/mL after a 50-mg dose. Plasma Aβ concentrations decreased in a dose-dependent manner over a 6-hour interval following drug administration, with a maximum decrease of approximately 40% relative to baseline. After returning to baseline, Aβ concentrations were transiently increased. CSF Aβ concentrations were unchanged. Adverse events reported by subjects taking 5-mg, 20-mg, or 40-mg doses were similar to those reported by subjects taking placebo. Two of 7 subjects taking 50 mg/day experienced adverse events that may have been drug related. In this phase 1 volunteer study, reported adverse events after taking LY450139 were manageable. A dose-dependent reduction in plasma Aβ was demonstrated, and changes in plasma A concentrations were temporally related to the pharmacokinetic characteristics of LY450139.

Original languageEnglish (US)
Pages (from-to)126-132
Number of pages7
JournalClinical neuropharmacology
Issue number3
StatePublished - May 1 2005


  • Alzheimer disease
  • Beta amyloid
  • Cerebrospinal fluid
  • Gamma secretase

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Clinical Neurology
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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