Truncated AUCs in the assessment of the bioequivalence of topiramate, a long half-life drug.

Author(s): Almeida S, Spinola AC, Filipe A, Trabelsi F, Farre A

Affiliation(s): Medical Department, Grupo Tecnimede S. A., Ed. Sagres 4oB, 2685-338 Prior Velho, Portugal. dmed.ct.tecnimede@mail.telepac.pt

Publication date & source: 2007, Arzneimittelforschung., 57(5):249-53.

Publication type: Randomized Controlled Trial

This study was conducted in order to assess the bioequivalence of two tablet formulations containing topiramate (CAS 97240-79-4), 25 mg. Twenty-four healthy volunteers were enrolled in an open-label, randomised, crossover, 2 periods x 2 sequences, with a minimum washout period of 21 days, single dose study. Blood samples were collected prior to study drug administration and 0.167, 0.333, 0.500, 0.667, 1.00, 1.33, 1.67, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 12.0, 24.0, 48.0, 96.0, 144, 192, and 264 h post-dose in each period. Plasma levels of topiramate from the 23 subjects who completed the study, were determined by high-pressure liquid chromatography with tandem mass detection, HPLC/MS/MS (lower limit of quantification 9.98 ng/mL). Pharmacokinetic parameters used for bioequivalence assessment (AUC(last), AUC(inf) and C(max)) were determined from the plasma concentration data using non-compartmental analysis. Mean +/- standard deviation elimination half-life for the reference formulation was 84.18 +/- 14.61h whereas for the test formulation it was 80.82 +/- 11.50h. The 90% Confidence Intervals (90 CI) were 98.00-111.35% for C(max), 98.44-103.76% for AUC(last) and 96.61-103.00% for AUC(inf), that is, within the ranges defined in the protocol for acceptance of bioequivalence. The 90 CIs obtained for the truncated AUCs were as follows: 100.27-105.32% for AUC0-48, 99.28-104.62% for AUC0-48, 99.13-104.56% for AUC0-96, 95.67-104.82% for AUC0-144, and 100.04-103.76% for AUC0-192. Both analysed formulations are bioequivalent irrespective of whether the conventional or truncated AUC approach is used. This study demonstrated that topiramate can be viewed as a long half-life drug and that the truncated AUC ap proach could be considered for bioequivalence assessment.