MULTIPLE-DOSE PHARMACOKINETICS AND SAFETY OF A POTENTIAL MEMORY-ENHANCING COMPOUND, CL-275,838, IN HEALTHY MALE-VOLUNTEERS

The pharmacokinetics and safety of CL 275,838, a new potential memory- enhancing compound, were examined after 14 daily doses (50 and 100 mg) in 16 healthy male volunteers, age 20 to 59 years, in a randomized, d ouble-blind, placebo-controlled, parallel group study. Trough blood sa mples (predose) were collected on days 2, 4, 7, 10, and 14, and furthe r samples were drawn after the final dose (day 14) to define the multi ple-dose kinetics of the parent compound and its metabolites II and IV . Intercurrent clinical events, vital functions, EEG, ECG, and cogniti ve tests (attention, verbal memory, and spatial memory) were considere d as outcome measures of safety. Performance in cognitive tests was al so studied to collect preliminary information on possible therapeutic action. Predose plasma concentrations of the parent compound and its t wo metabolites increased approximately in proportion to the dose, and accumulation was complete within 7 days, regardless of the dose. At st eady state, mean C-max and AUC of the parent compound and its two meta bolites were dose related. Mean wash-out t(1/2) was 18 to 20 hours for the parent compound, 22-23 hours for metabolite II, and 28-33 hours f or metabolite IV; these elimination t(1/2) are comparable for the two doses, and are similar to those observed in single-dose studies. For t he 50-mg-dose group, predicted and observed average plasma concentrati ons (Css) of CL 275,838 and its two metabolites did not differ signifi cantly. However, for the 100-mg-dose group, observed Css of CL 275,838 and its main metabolite, the desbenzyl derivative II, were slightly h igher than those predicted from the single-dose study, indicating a de viation from linearity after repeated higher oral doses. No major adve rse drug reaction was detected at either dosage, and there was no evid ence of CL 275,838-induced changes in hepatic parameters. Mild headach e occurred in three of the ten subjects given active treatment, withou t any clear relation with the dose. At 100 mg, a significant improveme nt of attention was observed. This is a preliminary, but encouraging, finding that indicates the usefulness of studying the safety and effic acy in an appropriate patient population.