Dotarizine is a new diphenylmethylpiperazine derivative with Ca2+ channel blocking properties and inhibitory effects on 5-HT2(A) and 5- HT2(C) receptors. Previous pilot studies in healthy volunteers demonstrated a good tolerability after single and multiple dosing. Dotarizine appeared to be rapidly and extensively metabolized to an active compound (FI-6020). We aimed to study the physiologic, subjective and psychomotor acute effects of oral dotarizine after single dose administration, to evaluate the tolerability and safety after multiple dosing over 2 weeks, and to study the pharmacokinetics parameters and linearity after single and multiple administration. Two different studies were carried out in 2 groups of 8 healthy male volunteers. Oral single doses of dotarizine 50, 100 and 200 mg were administered in a randomized, double-blind, crossover, placebo- controlled trial. Oral doses of 50 mg twice daily were administered in an open trial over 14 days. Drug effect assessments included vital signs, collection of adverse events, ECG and blood and urine safety evaluations, subjective effects, psychomotor performance task and blood sampling. Dotarizine and its metabolite were determined by gas chromatography with N-P detector. The results showed a good tolerability of dotarizine after single oral doses as well as multiple oral doses over 14 days. No clinically relevant adverse events were reported during the study. The highest single dose (200 mg) produced a slight increase in sedation-related symptoms as well as a slight impairment in psychomotor performance tasks. Dotarizine and its major metabolite proved linear kinetics at single doses. The administration of oral doses of dotarizine 50 mg b.i.d, reached the steady state after the 7th day of treatment. The pharmacokinetics parameters remained similar from day 7 to day 14. The terminal elimination half-life of dotarizine and its metabolite appeared to be between 7 and 12 h.
|Methods and Findings in Experimental and Clinical Pharmacology
|Published - 1 Oct 1997
- 5-HT antagonist 2
- Calcium channel blocker
- Phase I