RO-48-6791, A SHORT-ACTING BENZODIAZEPINE - PHARMACOKINETICS AND PHARMACODYNAMICS IN YOUNG AND ELDERLY VOLUNTEERS IN COMPARISON WITH MIDAZOLAM

The objectives of the present study were to compare in a randomized do uble-blind crossover study design the concentration-effect relationshi ps of Ro 48-6791, a new benzodiazepine agonist, and midazolam, followi ng infusion in young and elderly male volunteers. Therefore, linearly increasing plasma concentrations were generated by computer controlled infusion pumps to achieve a deep hypnotic effect. The endpoint of the infusion was defined by loss of response to loud verbal commands and a median frequency of the recorded EEG power spectrum below 4 Hz. Arte rial blood samples were collected in regular intervals up to 6 hours a fter cessation of the infusion. The method of pharmacokinetic-pharmaco dynamic modeling was used to quantify the concentration-effect relatio nship, including age related differences, already in this early phase I study. The total clearance of Ro 48-6791 was found to be 1410+/-380 vs. 399+/-91 ml min(-1) for midazolam (mean+/-SD; P<0.005) and the cen tral volume of distribution to be 20.5+/-7.1 vs. 7.9+/-3.01, respectiv ely (P<0.005). The comparison between young and elderly volunteers yie lded for Ro 48-6791 a statistically not significant reduction of 16% f or clearance with age and a slowed distribution of 47% for midazolam ( P<0.05). The recovery period for Ro 48-6791 was reduced by 66% (P<0.00 5) in the young and 45% (P<0.01) in the elderly, respectively, in comp arison with midazolam. With respect to the total doses administered, R o 48-6791 appeared to be 2.5 times as potent as midazolam in all volun teers (P<0.001). Comparing both age groups, the doses necessary to cau se similar effects were reduced by one half for both compounds in the elderly (P<0.001). The major advantages of Ro 48-6791 compared to mida zolam were its shorter duration of action as well as the faster recove ry and thus the better controllability. Further investigations would h ave to confirm these results in a greater number of patients. The appl ied method of pharmacokinetic-pharmacodynamic modeling not only allowe d to quantify the efficacy of Ro 48-6791 but also provided data to aug ment the safety for fur ther investigations.