A double‐blind comparison of conventional and controlled‐release carbamazepine in healthy subjects.

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Abstract
Eight healthy subjects took part in a balanced, double-blind, crossover comparison of conventional carbamazepine (Tegretol, Ciba-Geigy Ltd, CBZ-C) and a novel controlled-release formulation (Tegretol CR Divitabs, Ciba-Geigy Ltd; CBZ-CR). An initial single dose of either preparation was followed 1 week later by a 2 week course of 200 mg twice daily. Following the single dose, CBZ-CR produced a concentration plateau from 6-56 h at 50-60% of the CBZ-CR peak. After 2 weeks'' treatment, CBZ daytime levels measured as area under the concentration-time curve over a dosage interval were 7% lower with CBZ-CR, but this difference was not statistically significant. CBZ-CR showed less diurnal fluctuation (12%) of CBZ than CBZ-C (24%; P < 0.025) with less rapid changes in concentration (P < 0.02). Diurnal fluctuation of free CBZ and of CBZ 10,11 epoxide, the active metabolite, did not differ significantly between the two preparations. Auto-induction of CBZ metabolism resulted from the administration of both formulations. The mean elimination half-life was 23 h (CBZ-C) and 25 h (CBZ-CR) after dose 29 compared with a base-line value of 37 h (both P < 0.02). Antipyrine metabolism was also induced to a similar extent in both legs of the study (P < 0.01). No significant alteration in psychomotor function was demonstrated with either preparation. CBZ-CR fulfills the criteria for a controlled-release preparation with comparable apparent bioavailability to CBZ-C. Further pharmacokinetic and, more importantly, pharmacodynamic studies are required in epileptic patients to confirm a clinical advantage over the currently available formulation.