PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE EEG EFFECTS OF RO-48-6791, A NEW SHORT-ACTING BENZODIAZEPINE, IN YOUNG AND ELDERLY SUBJECTS

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, t he pharmacokinetics and pharmacodynamics of Po 48-6791, a new water so luble benzodiazepine. A microprocessor-controlled i.v. infusion pump g enerated linearly increasing arterial plasma concentrations until pred etermined EEG and clinical end-points were attained. This concentratio n was maintained for 15 min and thereafter the infusion was discontinu ed. Haemodynamic and respiratory variables were monitored continuously . At full reorientation of the subject, a second infusion cycle was st arted under the same conditions to investigate the reproducibility of the concentration-effect relationship. The plasma concentration-time p rofiles of Ro 48-6791 were fitted accurately to an open three-compartm ent model. Plasma concentrations of Po 48-6792, an N-dealkylated metab olite, accumulated during the course of the study. Pharmacokinetic var iables of Po 48-6791 were similar for both groups. The largest differe nces between young and elderly subjects, respectively, were found for clearance (mean 85 (SD 23) vs 71 (15) litre h(-1)) and k(12) (11 (7) v s 7 (3) h(-1)). The concentration-median EEG frequency relationship wa s described with a sigmoid Emax model. Elderly subjects showed slightl y increased drug sensitivity compared with young subjects (EC50 72 (25 ) and 44 (15) mu g litre(-1) in young and elderly subjects, respective ly). The concentration-response data of the second infusion cycle devi ated from the fitted curve suggesting either development of acute tole rance 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 Po 48-6791 should be administered to elderly compared with young su bjects in order to achieve similar effects.