Single‐Dose Safety and Pharmacokinetics of a Potential Cognition‐Enhancing Compound, CL 275,838, in Healthy Volunteers

The pharmacokinetics and safety of CL 275,838, a potential cognition‐enhancing compound, were studied after single escalating oral doses first in young healthy male volunteers and then in old (60–74 years) and very old (over 75 years) volunteers of both sexes. In all age groups absorption of CL 275,838 was rapid as assessed by the mean time to reach maximum plasma concentrations (Cmax) which averaged 1–2 hr, regardless of the dose administered. In young male volunteers both Cmax and area under the curve (AUC) increased proportionally with dose from 10 to 100 mg. Mean elimination half‐lives (t1/2) of the parent compound (18–21 hr) and of its circulating metabolites II (20–22 hr) and IV (27–30 hr) were well comparable for the doses tested (50 and 100 mg). Age did not appreciably affect plasma Cmax of CL 275,838 or its two metabolites. Mean AUC and elimination half‐life did not appreciably differ between old and very old subjects given 50 mg CL 275,838, with the limitations dictated by the small number of elderly subjects examined. Compared with younger volunteers receiving comparable doses, however, the elderly had higher mean plasma AUC of the unchanged compound and its two metabolites, although the parameter varied widely between subjects. The mean elimination t1/2 (± SD) was longer in the elderly (38.8 ± 19.6, 50.5 ± 24.5 and 41.7 ± 12.1 hr, respectively, for the parent compound and its metabolites II and IV) than in the young subjects. The cause(s) of these variations and the possible clinical implications remain to be established. These preliminary findings showed that, after single oral doses, 1) CL 275,838 is rapidly absorbed, undergoes extensive biotransformation and forms active metabolites, as many lipophilic centrally acting drugs do; 2) it has linear kinetics, at least in young male volunteers in the range of oral aoses tested (10–100 mg) and 3) there may be some differences between its disposition in young and elderly subjects. No major side effects were detected up to doses of 50 mg in subjects aged 19 to 85 years, and up to 100 mg in young volunteers. Mild headache occurred in 13% and 5% after active treatment and placebo, respectively. A slight increase of alanine aminotransferase serum levels was reached in one subject given 50 mg of the test compound.