Abstracts

Rationale: Plasma concentrations of antiepileptic drugs (AEDs) can fluctuate between dosing intervals. This fluctuation can lead to increased side effects during peak concentration levels (C_max) or break-through seizures at the trough concentration (C_min). While dosing multiple times a day can reduce the time interval between drug intakes and minimize the fluctuations in plasma concentration, medication compliance may be lessened. Extended release (ER) formulations of AEDs that provide stable serum concentrations over time with less frequent treatment administration have been developed. Once-daily (QD) extended-release (ER) formulations of topiramate (TPM) were developed by USL to potentially address these concerns. The a priori pharmacokinetic (PK) goals of TPM ER QD formulations were: 1) C_max for TPM ER ? C_max for TPM immediate-release (IR) administered every 12 hours (q12h) at simulated steady-state (SS), 2) C_min for TPM ER ? C_min for TPM IR q12h at SS, 3) AUC_0-t for TPM ER that is equivalent for extent of exposure (90% confidence intervals [CI] between 80% - 125%) to TPM IR q12h at SS. Methods: Numerous TPM ER QD formulations were internally developed and evaluated in PK studies. All studies were single-dose, crossover designed trials comparing TPM ER test formulations to TPM IR. Each study included a 14-day PK sampling period. TPM concentrations were measured in plasma using High Performance Liquid Chromatography (HPLC) with Mass Spectrometry (MS)/MS detection. The PK parameters (C_max, AUC, T_max, t_1/2) were calculated at single-dose (SD) and at SS using PK data modeled to SS using nonparametric modeling. Additionally, C_min was determined from modeled SS data. Point estimates (PE) of the ratio between the test formulations and TPM IR with corresponding 90% CI were calculated. Results: PK studies showed that all of the formulations met one or more of the a priori PK goals. Several of the formulations, dosed QD, had C_max that were lower, C_min that were higher, and equivalent extent of exposure at modeled SS compared to TPM IR dosed q12h. Formulations with delayed T_max were found to be eliminated from the body prior to complete absorption of the active ingredient. Conclusions: It is possible to develop TPM ER QD formulations that have improved PK characteristics to TPM IR q12h.