• pharmacokinetics;
  • pharmacodynamics;
  • benzodiazepine;
  • midazolam;
  • Ro 48-6791

Aims This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48–6791, compared with midazolam, in healthy subjects during first administration to man studies.

Methods The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48–6791 was administered as a slow i.v. infusion in doses of 0.1–0.3–1 mg in the first group, and 1–2–3 mg in the second. Midazolam was infused at 0.1 mg kg−1. The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min−1 ) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (&bgr;-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling.

Results Ro 48–6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (Vss ) 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, respectively). The doses of Ro 48–6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48–6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in &bgr;-power than Ro 48–6791 at the highest administered dose. Ro 48–6792, a metabolite of Ro 48–6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48–6792 in the present study, the effects of possible accumulation during prolonged administration 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.