Daily fluctuation of plasma levels with conventional and controlled-release carbamazepine: correlation with adverse effects

The pharmacokinetics, tolerability, and efficacy of carbamazepine (CBZ) and the pharmacokinetics of carbamazepine-10, 11-epoxide (CBZE) were studied after chronic administration of a conventional tablet formulation or of the controlled-release (CR) formulation of CBZ 400 mg (Tegretol 400) to 20 patients with epilepsy treated with carbamazepine and complaining of intermittent adverse effects. To compare the two formulations at the same doses and dose schedules, the study design had to be open, within-patient, with an initial 4 week period to individually adjust the dosage schedule with conventional CBZ followed by a 4 week period in which the CR formulation was substituted for conventional CBZ at the same daily dose and given by the same schedule. A further 4 week period was also studied to evaluate the same dosage of the CR formulation but given b.i.d. In this latter period six patients required an increase in dosage (200 mg/day). Before the beginning of the study and at the end of each period seizure frequency and tolerability were assessed. Tolerability was estimated with a specifically prepared scale that assesses the main items and with an overall rating scale. At the end of each treatment period, serum levels of CBZ and CBZE were determined at various times over a 10 h period. Peak plasma concentrations (Cmax) of CBZ and the fluctuation index (FI) were significantly lower for the CR CBZ, although minimal and mean plasma concentrations were the same in the three periods of the study. The number of patients with and without seizures and the number of seizures in poorly controlled patients did not differ significantly in the three periods, but the number of patients with adverse effects decreased significantly with CR CBZ. The incidence and the severity of diplopia, vertigo and nystagmus correlated with the FI and/or the Cmax of CBZ, being greater in patients with a Cmax over 8 μg/ml or an FI over 25%.