INTEGRATED PHARMACOKINETICS AND PHARMACODYNAMICS OF RO-48-6791, A NEWBENZODIAZEPINE, IN COMPARISON WITH MIDAZOLAM DURING FIRST ADMINISTRATION TO HEALTHY MALE-SUBJECTS

Aims This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48-671, compared with midazo lam, in healthy subjects during first administration to mall studies. Methods The study was double-blind and five-way crossover with treatme nt on 5 consecutive days (three ascending doses, placebo, fixed midazo lam dose) in two sequential groups of five healthy male subjects. Ro 4 8-6791 was administered as a slow i.v. infusion in doses of 0.1-0.3-1 mg in the first soup, and 1-2-3 mg in the second. Midazolam was infuse d at 0.1 mg kg. The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min) differed considerably among doses. Blood sampl es were collected frequently for pharmacokinetic determinations (two-c ompartment model). Pharmacodynamics were assessed by recording of sacc adic eye movements (saccadic peak velocity) and electroencephalography (beta-power). These parameters were used for pharmacokinetic/pharmaco dynamic modelling.Results Ro 48-6791 and midazolam were both well tole rated. Most clinical events were dose-dependent central depressant eff ects. The volume of distribution (V-ss) and plasma clearance of Ro 48- 6791 were on average markedly larger than those of midazolam (171 +/- 65 vs 41 +/- 10 l and 2.2 +/- 0.9 vs 0.42 +/- 0.11 l min(-1), respecti vely). The doses of Ro 48-6791 leading to loss of saccadic eye movemen ts were on average four times lower than that of midazolam. The corres ponding predicted effect compartment concentrations differed by a fact or of about six. Doses of Ro 48-6791 and midazolam eliciting similar m aximum effects had a comparable onset and duration of action fbr sacca dic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in beta-power than Ro 48-6791 at the highest admini stered dose. Ro 18-6792, a metabolite of Ro 48-6791, showed a consider ably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48-6792 in the present stud y, the effects of possible accumulation during prolonged administratio n should be investigated further. Conclusions This first study with Ro 48-6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.