Multiple-dose tolerability, pharmacodynamics, and pharmacokinetics of the quinolizinone hypnotic Ro 41-3696 in elderly subjects

The objectives of this double-blind, placebo-controlled study were to assess the multiple-dose tolerability, pharmacodynamics, and pharmacokinetics of the hypnotic agent Ro 41-3696 in elderly men and women (55-75 y of age). On day 1 and days 3-8, doses of 1, 3, 5, and 10 mg were administered sequentially to 4 groups of 10 subjects, 2 of whom received placebo. Psychomotor performance tests (tracking and attention) were conducted just before and at 1.5, 4, and 8 hours after drug intake on days 1, 4, 6, and 8. Memory was assessed at 24 hours after drug intake on days 1 and 8 by recall of a list of 10 words, which had been learned at 2 hours after intake. Ro 41-3696 was well tolerated at all dose levels. One subject dropped out of the study because of a hypersensitive skin reaction during treatment with 10 mg. Performance in both a tracking test and a memory search test was significantly affected by a dose of 10 mg and moderately affected by doses of 3 and 5 mg. The results of the 1-mg dose were indistinguishable from those of placebo. Long-term memory, as assessed by a word learning and recall test, showed the same pattern. Partial tolerance to the impairing effects in the psychometric tests developed over the course of treatment. Pharmacokinetics of both Ro 41-3696 and its O-desethyl metabolite Ro 41-3290 were dose proportional and time independent. Ro 41-3696 was absorbed and eliminated rapidly (time of maximum plasma concentration, approximately 1 hour; elimination half-life, approximately 2 hours). Plasma levels of Ro 41-3290 were higher than those of the parent drug, and it was more slowly eliminated (values for time of maximum plasma concentration and elimination half-life, approximately 2 and approximately 7 hours, respectively).