Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.
OBJECTIVE
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 (beta-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 (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), 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 beta-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.
Dingemanse
J
J
Department of Clinical Pharmacology, F.Hoffmann-La Roche Ltd, Basel, Switzerland.
van Gerven
J M
JM
Schoemaker
R C
RC
Roncari
G
G
Oberyé
J J
JJ
van Oostenbruggen
M F
MF
Massarella
J
J
Segala
P
P
Zell
M
M
Cohen
A F
AF
D000759:Adjuvants, Anesthesia / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001569:Benzodiazepines; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology*
D000759:Adjuvants, Anesthesia; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; C104519:Ro 48-6791; D008874:Midazolam