Abstracts

Ucb 34714 is an investigational new drug structurally related to levetiracetam (LEV) with a higher affinity and similar high selectivity towards the brain-specific LEV binding site. The anticipated pharmacologically active dose in humans is around 150 mg based on animal models of epilepsy. Single and repeated oral administration of ucb 34714 were performed in a Randomized, double-blind, placebo controlled manner. Healthy male volunteers were enrolled. For the single administration, 3 alternating panels of 9 subjects received the following doses: 10, 20, 40, 80, 150, 300, 600, 1000, and 1400 mg (6 active: 3 placebo). For the multiple dose administration, 3 different panels of 12 subjects (9 active: 3 placebo) received 200, 400 and 800 mg/day in 2 daily doses during 2 weeks. CNS effects were explored with psychomotor tests and rating scales. The food effect was also assessed after single administration of 150 mg to 8 subjects in a 2-way cross-over design. During single and repeated administrations, there was a dose-related increase in the frequency of CNS adverse events of which the commonest were dizziness, somnolence and euphoria. Adverse events were mild or moderate and resolved within the first day of treatment.
After single intake of ucb 34714, 25 of 27 subjects reported 56 adverse events. None were serious. The most frequent adverse events were dizziness (12/27), somnolence (9/27) and euphoric mood (3/27). One subject had severe somnolence after intake of 1400 mg. 1000 mg was then set as the maximal tolerated dose (MTD) in this population.
During multiple administrations, the adverse events reported in more than one patient were dizziness (17/27), somnolence (7/27), headache (7/27), euphoric mood (5/27), throat irritation (4/27), fatigue and nausea (3/27), blurred vision, feeling drunk, agitation and hypotension (2/27). There were no serious adverse events. There were no clinically significant abnormalities reported from neurological examinations, psychomotor tests or rating scales, clinical laboratory, vital signs, ECGs and physical examination. The MTD was not reached after 14 days at 800 mg/day.
Ucb 34714 was rapidly absorbed and followed first-order single compartment kinetics over a wide range of doses. The half life was 7 hours on average. The steady state was reached within 1 week. Ucb 34714 was rapidly excreted in the urine. When administered with food, Cmax was reduced by 28% while AUC was not altered. The MTD of ucb 34714 is 1000 mg after single dose and more than 800 mg/day after 2 weeks of repeated dosing. The main adverse events are dizziness and somnolence. The pharmacokinetic steady state is reached within one week. (Supported by UCB Pharma SA)