INTEGRATED PHARMACOKINETICS AND PHARMACODYNAMICS OF RO-48-8684, A NEWBENZODIAZEPINE, IN COMPARISON WITH MIDAZOLAM DURING FIRST ADMINISTRATION TO HEALTHY MALE-SUBJECTS

Aims This study aimed to investigate the pharmacodynamics and pharmaco kinetics of ascending doses of Ro 48-8684, compared with midazolam, in healthy subjects during first administration to man. Methods The stud y was double-blind and five-way crossover (three ascending doses, plac ebo, fu;ed midazolam dose), performed in two groups of five males. Ro 48-8684 was infused in doses of 0.1-0.3-1 mg ill the first group, and 1-3-10 mg in the second, with different infusion rates (expressed as m g min(-1)) among doses. Midazolam was infused ar 0.1 mg(-1) kg. infusi ons were stopped after 20 min or if sedation became too strong for pro per performance of saccadic eye movements. Pharmacokinetics and pharma codynamics and their relationships were evaluated as described in the companion article. Results Ro 48-8684 caused dose-dependent sedation. No serious adverse events occurred. The volume of distribution and cle arance of Ro 48-8684 were larger than of midazolam (337+/-114 vs 50+/- 121 and 2.4+/-0.5 vs 0.47+/-0.11 l min(-1), resp). The recovery of sac cadic eye movements from equal levels of sedation was on average almos t half an hour faster for Ro 48-8684 than for midazolam, with consider able interindividual differences (range 2, 55 min). The doses of Ro 48 -8684 leading to the same clinical endpoint as midazolam were comparab le, but the corresponding predicted effect compartment concentrations of Ro 48-8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the Linear concentration-effect-relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48-8684 t han for midazolam (range 1.3, 3.3). The slope decreased on average 4.4 -fold (range 1.6, 7.3 times), with doses of Ro 48-8684 increasing from 1 to 10 mg. The metabolite Ro 61-2466 had a longer half-life than the parent compound Ro 48-8684. The ir-fluence of this metabolite during prolonged administration should be further investigated. Conclusions T hese results show that Ro 48-8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to R o 48-8684 with repeated administration of rising doses due to as yet u ndetermined factors.