Abstracts

Rationale: The bioavailability of oral drugs can be influenced by the presence of food. Food can influence absorption of the drug as a result of changes in the gastrointestinal tract or from a direct interaction between the food and the drug. Upsher-Smith Laboratories, Inc. (USL) has recently developed USL255, a novel extended-release formulation of topiramate. This formulation will allow for once daily dosing and may result in diminished fluctuations in plasma concentration, and an improved adverse event profile. Previous pharmacokinetic studies of immediate release topiramate (TPM IR tablet; Topamax ) found that food has no effect on bioavailability; however, the effect of food on USL255 has not yet been reported. Methods: The pharmacokinetic (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). The effect of consuming a standardized high-fat breakfast was assessed using standard bioequivalence criteria. The a priori criterion for the lack of food effect was defined as a 90% confidence interval (CI) of the ratio of the geometric least square mean for AUC_0-? and C_max (USL255_fed/USL255_fasted) that fall within the critical range of 0.8 - 1.25. Results: The 90% CI for the ratio of geometric least square means of both AUC_0-? (0.99 [90% CI; 0.89 - 1.09]) and C_max (0.97 [90% CI; 0.90 - 1.04]) were contained within the critical range, indicating that the presence of food had no significant effect on USL255 bioavailability. T_max was significantly increased in the fed state (24 hr) versus the fasted state (20 hr; P = .04). Furthermore, USL255 was found to be well-tolerated in both fasting and fed conditions. Conclusions: Results from this initial pharmacokinetic study in healthy volunteers indicate that USL255 is well tolerated and that the overall bioavailability of USL255 is not affected by food; however, the presence of food may slow the time to maximal plasma concentration.