Pharmacokinetics of a New Anticonvulsant (CGP 33101) in Epileptic Male Patients and Healthy Male Subjects after Single Ascending Oral Doses of 400--1200 mg.

Abstract

Information on the pharmacokinetic behavior of a new anticonvulsant agent (CGP 33101) was obtained after oral administration of ascending doses to male epileptic patients maintained on existing antiepileptic drug (AED) therapy, as well as to healthy male subjects. Single doses of 400, 800 and 1200 mg were administered to 12 of the 16 epileptic patients participating in the clinical trial and all 3 healthy subjects; the remaining patients received placebo doses on each dosing occasion. The study's primary objectives were to obtain single-dose add-on tolerability information, as well as preliminary pharmacokinetic data for the drug candidate. Either placebo or 400, 800 and 1200 mg of the compound, administered as 200-mg tablets, were coadministered with enzyme-inducing antiepileptic medications to the patients participating in the trial. These AEDs dilantin, tegretol, depakote, mysoline and tranxene) were administered individually or as combination therapy of two or three, with each patient being on the existing therapy for a minimum of 3 weeks prior to receiving the drug candidate (CGP 33101) as an add-on. Three healthy male subjects were included in the study to provide concurrent pharmacokinetic data at equivalent doses, as well as additional safety data in the absence of concomitant medication. Plasma concentrations of the new drug candidate were determined in samples obtained predose through 120-h postdose, with a 5-day washout period between doses. Preliminary pharmacokinetic parameters, such as peak plasma concentrations (C(max), times to peak levels (T(max)), areas under the plasma concentration-time curve (AUC) and terminal half-lives (T(1/2)), were determined in both epileptic patients and healthy subjects following all three doses. The mean T(max) values were similar for all three dose levels in both patients and subjects, indicating that the rate of absorption was comparable. Mean C(max) values increased in a dose-related manner with increasing dose in epileptic patients. The corresponding values showed a dose-proportional relationship in healthy subjects. The relationship between C(max) values and the administered dose did not change in patients or subjects when the data was corrected for dose and/or body weight. After the peak, plasma levels declined, but were still quantifiable in most patients and subjects at 36 h following all three doses. The mean AUC values increased in a dose-proportional manner with increasing dose in healthy subjects. The corresponding mean patient data appeared to increase in a dose-related manner. The relationship between AUC values and size of the administered dose did not change in either patients or subjects when the data was corrected for dose and/or body weight. The terminal elimination half-lives (T(1/2)) were apparently shorter in patients compared to the healthy subjects and were independent of the close administered.