Bioequivalence of carbamazepine chewable and conventional tablets: Single-dose and steady-state studies

Article abstract of DOI:10.1002/jps.2600740813

Single-dose and steady-state studies were carried out on separate occasions to examine the bioequivalence of the newly formulated carbamazepine chewable tablet. In the single-dose study, the plasma levels resulting from 2 x 200-mg conventional tablets (CT), 4 x 100-mg chewable tablets swallowed whole (SW), and 4 x 100-mg chewable tablets chewed before swallowing (CHEW) were compared. A randomized 3 x 3 Latin-square design balanced for residual effects, with a 3-week washout period, was used (n = 6). Plasma samples were analyzed by a specific GC method for carbamazepine. The following parameters were used for evaluation: AUC, C(max), t(max), and t( 1/2 ). None of the parameters were significantly different except C(max) and t( 1/2 ) values for CHEW and CT. The C(max) was 25% higher and t( 1/2 ) was 11% shorter for CHEW than CT. The impact of differences in the peak plasma levels at steady state were examined by pharmacokinetic projection (400 mg b.i.d.) based on the single-dose data and with simulated induction equal to a 50% reduction in t( 1/2 ). The projected steady-state CT and CHEW plasma concentrations were similar, with a difference of only 4%. The results demonstrate the bioequivalence of the dosage forms with respect to the extent of absorption, and similar steady-state concentrations of carbamazepine in plasma can be expected. To test the conclusion from the projected study, a separate bioequivalence study to compare CHEW relative to CT was performed at steady state in normal volunteers (200 mg b.i.d.). A randomized 2 x 2 crossover design was used, with each formulation being administered for 24 d followed by a 5-d sample collection period (n = 9). The plasma samples were analyzed by a specific HPLC assay for carbamazepine (CBZ) and the epoxide metabolite (CBZE). Predose levels (days 22-24) were not significantly different for either formulation. In addition, no period effect was observed on the t( 1/2 ) of CBZ or on the metabolite fraction, indicating that induction was in a stable state and that steady state for CBZ plasma levels was reached. Again, the results demonstrate that both formulations delivered equal amounts of CBZ to the systemic circulation. The average C(max) of CBZ for CHEW was 7% higher (6.4 versus 6.0 μg/ml) and the median t(max) was slightly shorter (2.0 versus 3.0 h) than that for CT, but the differences were not significant. The results are in close agreement with those estimated in the projected study.