Safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ascending multiple doses of SRA‐333 in healthy subjects

SRA-333 is a new potent and silent 5HT1a antagonist which increased glutamatergic and cholinergic neurotransmission during cognitive processes. SRA-333 is proposed for the treatment of cognitive deficits associated with Alzheimer's disease. This was a randomized, double-blind, placebo-controlled, sequential, ascending multiple dose study conducted in 41 young adult and 8 elderly subjects. Doses of 0.1, 0.25, 0.5, 1 and 5 mg q12h (young) and 0.5 mg q12h (elderly) were administered for 14 days in cohorts of 8 subjects (6 active and 2 placebo). Assessments consisted of safety evaluation (vital signs, ECG, lab tests), up to 48 hours after the last dosing, determination of a complete PK profile on days 1 and 14 and cognitive assessment using the Cognitive Drug Research battery (Reading, UK) exploring attention, sensori-motor tasks and working and episodic memory. SRA-333 was safe and well-tolerated. No consistent, severe or dose-related adverse events were observed. No clinically significant changes were recorded in vital signs, ECGs and routine laboratory tests. No clinically relevant cognitive impairment were observed. SRA-333 was rapidly absorbed (tmax ≃1h) and eliminated (half-life ≃6h). Plasma concentrations exhibited approximately linear dose-proportionality over the dose range of 0.1 to 5 mg and mean steady state AUC 0–12h was within 20% of the single dose AUC 0-4, indicating linear drug accumulation with repeated administration. In the elderly, steady state Cmax and AUC were moderately higher (48 and 42%) than for the young subjects. No gender PK differences were observed. In summary, SRA-333 was safe and well-tolerated up to a daily dose of 10 mg for 14 days. Its pharmacokinetic profile allowed a twice daily dosage regimen. Clinical Pharmacology & Therapeutics (2004) 75, P21–P21; doi: 10.1016/j.clpt.2003.11.081