ABSTRACT
This positron emission tomography (PET) study was conducted to assess binding of lecozotan, a new potent and silent 5-hydroxytryptamine-1A (5-HT1A) antagonist being developed for the treatment of Alzheimer's disease (AD), to 5-HT1A receptors in the human brain using 11C-labeled WAY-100635. Lecozotan was administered as a single dose of 0.5, 1, or 5 mg to young subjects and 5 mg to elderly subjects and AD patients. PET measurements were performed at 3-4 time points over a 25-h period. Mean peak 5-HT1A receptor occupancy (RO) in young subjects (seen at 1 h) was 10%, 18%, and 44% for the three doses, respectively. Mean peak RO was slightly higher in elderly (63%) and AD patients (55%). An Emax pharmacokinetic/pharmacodynamic model adequately described the lecozotan plasma concentration-RO relationship. Steady-state peak RO is predicted to be approximately 70% for 5 mg q12 h (twice-daily). Results demonstrate that lecozotan binds to the human brain 5-HT1A receptors and has a maximum observed RO of 50-60% following a single dose of 5 mg in elderly subjects/AD patients.
Subject(s)
Aging/metabolism , Alzheimer Disease/metabolism , Brain/metabolism , Dioxanes/metabolism , Piperazines/metabolism , Positron-Emission Tomography , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Antagonists/metabolism , Administration, Oral , Adult , Aged , Aged, 80 and over , Alzheimer Disease/diagnostic imaging , Brain/diagnostic imaging , Brain/drug effects , Carbon Radioisotopes , Computer Simulation , Dioxanes/administration & dosage , Dioxanes/adverse effects , Dioxanes/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Models, Biological , Piperazines/administration & dosage , Piperazines/adverse effects , Piperazines/pharmacokinetics , Protein Binding , Pyridines , Radiopharmaceuticals , Serotonin 5-HT1 Receptor Antagonists , Serotonin Antagonists/administration & dosage , Serotonin Antagonists/adverse effects , Serotonin Antagonists/pharmacokinetics , Time FactorsABSTRACT
First human administration of a new chemical entity (NCE) constitutes a critical step in drug development. The primary objective of such a study is the assessment of the shortterm safety and tolerability of single and multiple doses of the NCE in healthy volunteers. Secondary objectives are to obtain preliminary data on the pharmacokinetics and pharmacodynamics using surrogate or biornarkers of the beneficial as well as the adverse effects of the drug. Interpretation of safety data should be cautious and mainly based on comparisons with placebo. A special focus should be made on the assessment of adverse events, liver enzymes, and cardiac repolarization. Well-designed, first-time-to-man studies should determine the safety of the NCE in humans and predict the dose range that may be used to safely and accurately conduct further clinical trials in the target patient population based on safety data (maximum tolerated dose), pharmacodynamics (minimum active dose, duration of action, and dosage regimen), and pharmacokinetics (dosage regimen).
