title: Pharmacokinetic-pharmacodynamic modelling of the EEG effects of Ro 48-6791, a new short-acting benzodiazepine, in young and elderly subjects.
abstract: The objectives of this study were to explore, by a modelling approach, in nine young (24-28 yr) and nine elderly (67-81 yr) male subjects, the pharmacokinetics and pharmacodynamics of Ro 48-6791, a new water soluble benzodiazepine. A microprocessor-controlled i.v. infusion pump generated linearly increasing arterial plasma concentrations until predetermined EEG and clinical end-points were attained. This concentration was maintained for 15 min and thereafter the infusion was discontinued. Haemodynamic and respiratory variables were monitored continuously. At full reorientation of the subject, a second infusion cycle was started under the same conditions to investigate the reproducibility of the concentration-effect relationship. The plasma concentration-time profiles of Ro 48-6791 were fitted accurately to an open three-compartment model. Plasma concentrations of Ro 48-6792, an N-dealkylated metabolite, accumulated during the course of the study. Pharmacokinetic variables of Ro 48-6791 were similar for both groups. The largest differences between young and elderly subjects, respectively, were found for clearance (mean 85 (SD 23) vs 71 (15) litre h-1) and k12 (11 (7) vs 7 (3) h-1). The concentration-median EEG frequency relationship was described with a sigmoid Emax model. Elderly subjects showed slightly increased drug sensitivity compared with young subjects (EC50 72 (25) and 44 (15) micrograms litre-1 in young and elderly subjects, respectively). The concentration-response data of the second infusion cycle deviated from the fitted curve suggesting either development of acute tolerance to the EEG effects of Ro 48-6791 or a role for drug metabolites. Because of the differences in sensitivity and clearance, lower doses of Ro 48-6791 should be administered to elderly compared with young subjects in order to achieve similar effects.
authors.affiliation: Department of Clinical Research, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Dingemanse
authors.forename: J
authors.initials: J
authors.lastname: Häussler
authors.forename: W
authors.initials: W
authors.lastname: Hering
authors.forename: H
authors.initials: H
authors.lastname: Ihmsen
authors.forename: S
authors.initials: S
authors.lastname: Albrecht
authors.forename: M
authors.initials: M
authors.lastname: Zell
authors.forename: H
authors.initials: H
authors.lastname: Schwilden
authors.forename: J
authors.initials: J
authors.lastname: Schüttler
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D001569:Benzodiazepines / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004569:Electroencephalography / Q000187:drug effects*; D006801:Humans; D008297:Male; D008954:Models, Biological
chemical_list: D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; C104519:Ro 48-6791