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Pharmacokinetics and Pharmacodynamics of Ro 41–3696, a Novel Nonbenzodiazepine Hypnotic
Author(s) -
Dingemanse Jasper,
Bury Michèle,
Roncari Gaetano,
Zell Manfred,
Gieschke Ronald,
Gaillard Anthony W. K.,
Odink Jaap,
Brummelen Peter
Publication year - 1995
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1995.tb04126.x
Subject(s) - pharmacokinetics , tolerability , medicine , hypnotic , pharmacology , pharmacodynamics , placebo , agonist , receptor , adverse effect , alternative medicine , pathology
This report describes the first evaluation in humans of Ro 41–3696. Based on its preclinical profile, Ro 41–3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo‐controlled, double‐blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41–3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41–3696 was absorbed and eliminated rapidly (t max = ∼1 hour; t 1/2 = ∼4 hours). At all times plasma levels of Ro 41–3290, the desethylated derivative of Ro 41–3696, were higher than those of the parent drug (t max and t 1/2 values = ∼2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose‐proportional pharmacokinetics for both Ro 41–3696 and Ro 41–3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long‐term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41–3696 in doses up to ∼5 mg and further exploration of the characteristics of Ro 41–3290.