Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects

Br J Clin Pharmacol. 2009 Mar;67(3):299-308. doi: 10.1111/j.1365-2125.2008.03348.x.


Aims: To determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral immediate release (IR) lecozotan in healthy young and elderly subjects.

Methods: Three randomized, double-blind, placebo-controlled, sequential, ascending dose Phase I studies of lecozotan were conducted. In a single-dose study, ascending doses of 2, 5 and 10 mg were administered to cohorts of eight young subjects. In the two ascending 14-day multiple-dose studies, 41 young subjects received 0.1, 0.25, 0.5, 1 and 5 mg q12h of lecozotan or placebo and 24 elderly received 0.5 mg and 5 mg q12h of lecozotan or placebo. Assessments included safety evaluations, a complete PK profile and PD.

Results: Lecozotan was safe and well tolerated at steady state up to 5 mg q12. The maximum tolerated dose after multiple doses was >10 mg (5 mg q12). In the single-dose study, the maximum tolerated dose was 10 mg. Dose-limiting mild-to-moderate adverse events included paraesthesia, dizziness and visual disturbances peaking at t(max) and disappearing concomitantly with plasma concentrations. No clinically relevant changes in vital signs, ECG intervals or routine laboratory tests occurred. Lecozotan did not significantly change cognitive function, EEG or hormone levels. PK was characterized by rapid absorption, dose proportionality, extensive distribution and rapid elimination. The mean CL/F was approximately 35% lower in the elderly.

Conclusions: Lecozotan IR was safe and well tolerated after administration of multiple oral doses up to 5 mg q12h in young and elderly subjects. These results support the development of lecozotan in patients with Alzheimer's disease.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Alzheimer Disease / drug therapy*
  • Dioxanes / administration & dosage
  • Dioxanes / adverse effects*
  • Dioxanes / pharmacokinetics
  • Dioxanes / pharmacology
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Nootropic Agents / adverse effects*
  • Nootropic Agents / pharmacokinetics
  • Nootropic Agents / pharmacology
  • Piperazines / administration & dosage
  • Piperazines / adverse effects*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Serotonin 5-HT1 Receptor Antagonists*
  • Serotonin Antagonists / adverse effects*
  • Serotonin Antagonists / pharmacokinetics
  • Serotonin Antagonists / pharmacology
  • Treatment Outcome
  • Young Adult


  • Dioxanes
  • Nootropic Agents
  • Piperazines
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists
  • lecozotan