Abstracts

The aim of the study was to investigate the absorption characteristics of a new modified release dosage form of oxcarbazepine after once daily (OD) or twice daily (bid) application in comparison to an immediate release reference formulation during steady state conditions., Using an open three-period crossover design, 3 different treatments were examined after multiple dose administration of oxcarbazepine to 18 healthy male subjects. The test formulations administered were either oxcarbazepine modified release [OXC MR] 600 mg OD or 300 mg bid. The immediate release formulation of oxcarbazepine [OXC IR] 300 mg bid served as the reference formulation. The three treatments were administered during an up-titration phase of 6 days. Plasma concentration profiles were measured on day 7 during a 24-hour interval at different time points. A wash-out period of 14 days elapsed between the periods. Monohydroxycarbamazepine [MHD], the active metabolite of oxcarbazepine as well as the prodrug oxcarbazepine [OXC], were determined in EDTA plasma samples by a validated HPLC method with UV detection., The results of the multiple dose study demonstrated the consistency of the absorption of the primary parameter MHD from the novel OXC MR formulation after OD or bid application. The time concentration profiles following bid administration of 300 mg OXC MR showed that the mean extent parameters for absorption of MHD are equivalent with the OXC IR reference preparation. Results for peak trough fluctuation [PTF] indicate that fluctuation is reduced in the case of the OXC MR formulation [PTF=39% for OXC MR and 54% for OXC IR]. In addition, C[sub]min[/sub] concentrations of MHD were 10% higher and C[sub]max[/sub] concentrations were 6% lower after OXC MR bid compared to the respective results for OXC IR bid. Furthermore, confidence intervals for the extent of absorption [AUC] demonstrated equivalence between OXC MR 600 mg OD and OXC MR 300 mg bid [AUC: 87-96% ] or OXC MR 600 mg OD and OXC IR 300 mg bid [AUC: 88%-97%]. The confidence intervals met the commonly accepted range for bioequivalence of 80-125%., The newly developed OXC MR formulation exhibit appropriate modified release characteristics with similar extent of exposure [AUC], reduced peak plasma concentrations [C[sub]max[/sub]] and reduced PTF for the major active metabolite MHD compared to the IR formulation when applied twice daily. From C[sub]min[/sub]-values observed in this study it may be concluded that effective concentrations should be maintained over the entire dosing interval at steady state.
Moreover, the OXC MR formulation seems suitable also for once daily dosing in individual cases and therefore improves patient compliance., (Supported by Desitin Arzneimittel GmbH, Hamburg, Germany.)