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 in 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. The pharmacokinetic (PK) characteristics of USL255, a novel ER formulation of topiramate developed by Upsher-Smith Laboratories, Inc., were compared to immediate-release topiramate (TPM IR tablet; Topamax ). Methods: PK parameters of USL255 were investigated in a phase I, randomized, single-center, single-dose, open-label, 3-way crossover study. USL255 200 mg administered in the fasted condition (overnight fast ?10 hrs), USL255 200 mg administered in the fed condition (standard high-fat breakfast), and TPM IR 100 mg (b.i.d.) were evaluated. A Williams (6-sequence, 3-period) study design was used to randomize subjects (N = 36) to 1 of 6 treatment sequences, with 6 subjects per sequence. Following treatment, subjects entered a 3-week washout period during which blood samples were collected on the first 14 days. Plasma topiramate concentrations were determined using High Performance Liquid Chromatography (HPLC) with Mass Spectrometry (MS)/MS detection. PK parameters evaluated include maximum plasma concentration (C_max), time to peak plasma concentration (T_max), area under the plasma concentration-time curve extrapolated to infinity (AUC_0-?), and half-life (t_1/2). To show equivalence of topiramate exposure, the 90% confidence interval (CI) of the ratio of the geometric least square means (USL255/TPM IR) for AUC_0-? must be contained within the standard critical range (0.8 - 1.25). Similarly, the upper limit of the 90% CI of the USL255/TPM IR ratio for C_max should be less than 1.25. Results: Topiramate exposure did not differ between USL255 and TPM IR formulations. The 90% CI for the ratio of geometric least square means for AUC_0-? (0.91 [90% CI; 0.87-0.95]) was found to fall within the critical 0.8 - 1.25 range. In addition, the upper limit of the 90% CI of USL255/TPM IR ratio for C_max was less than 1.25 and the point estimate ratio was less than 1.0 (0.70 [90% CI; 0.65-0.74]), indicating that USL255 has a lower C_max than TPM IR. TPM IR achieved T_max 2 hrs after administration of the second dose (14hr) and the T_max for a single dose of USL255 was approximately 20 hrs. USL255 and TPM IR were both well-tolerated by the healthy volunteers who participated in this study. Conclusions: A single-dose of USL255 demonstrated exposure of topiramate equal to TPM IR but had a lower maximum plasma concentration than TPM IR. Taken together, these data suggest USL255 may improve upon the PK profile of the currently available IR formulation.