Bioavailability study of two carbamazepine containing sustained release formulations after multiple oral dose administration

Carbamazepine (CAS 298-46-4), an iminostilbene derivative and a structural congener of the tricyclic antidepressant drugs, has been used in the treatm ent of epileptic seizures since 1963. The bioavailability/bioequivalence of a carbamazepine sustained release formulation (Timonil(R) retard) was comp ared with a reference formulation in an open 2-period crossover study in 21 healthy male volunteers (including 1 drop-out) after multiple dose adminis tration. During a run-in phase of 6 days the daily dose was gradually incre ased from 100 to 400 mg. On days 9 to 15, either the test or the reference formulation was administered twice daily, followed by a switch of preparati on for a further 7 days of treatment (days 16 to 22). On the pharmacokineti c profiling days 15 and 22 blood samples were drawn over a 24-h period. In addition, blood samples were withdrawn before morning administrations for d etermination of carbamazepine and carbamazepine-10,11-epoxide trough values . Plasma concentrations of carbamazepine and its metabolite carbamazepine-1 0,11 -epoxide were determined using a specific and sensitive HPLC method wi th UV detection. The results showed that autoinduction of carbamazepine met abolism under the chosen dosage regimen was complete within 14 days after s tart of treatment and that the criteria for bioequivalence were met. The 90 % confidence intervals of all ratios were included by a range of 80-125% (A UC(0-12): 103-120; AUC(12-24); 105-119; Cmax0-12: 104-118; Cmax12-24: 104-1 18). During the study, 12 subjects experienced a total of 24 adverse events with mild to moderate intensity. Due to a significant increase of liver en zyme activity in serum during the course of the study, one subject was excl uded from further study participation. There were no serious adverse events . It was concluded that the test formulation is bioequivalent to the refere nce formulation with respect to rate and extent of absorption.