Abstracts

Rationale: Upsher-Smith Laboratories, Inc. has developed USL255, a novel, once-daily, extended-release formulation of topiramate (TPM). During development, the steady-state (SS) pharmacokinetic (PK) profile of USL255 was modeled using data from single-dose studies. The modeled data suggested that at SS, once-daily USL255 may provide TPM exposure equivalent to immediate-release topiramate (TPM IR) dosed twice-daily, with a lower C_max, higher C_min, and a reduced fluctuation index (FI). The objective of this study was to compare the SS PK profile of USL255 to TPM IR in healthy individuals. Methods: In this Phase I, open-label, 2-way crossover study, healthy subjects (N=38) were randomly assigned 1:1 to either USL255 once-daily or TPM IR every 12 hours. Subjects were up-titrated (Day -12 to -1) to a total of 200 mg of study drug, which was maintained through Period 1 (Day 1 to 14). On Day 15, subjects were immediately crossed over, without washout, to the alternate formulation for Period 2 (Day 15 to 28), and then down-titrated off study drug over 8 days (Day 29 to 36). Blood samples were collected throughout the study to determine SS PK parameters including AUC_0-24, C_avg, C_max, C_min, T_max, FI, and time to achieve SS TPM plasma concentrations. The requirement for PK equivalence between formulations was met if the 90% confidence interval (CI) of the ratio of the geometric least-squares mean (GLSM) between USL255 and TPM IR was completely contained within the equivalence limits of 0.8 1.25. Time to SS was estimated by using the Helmert Contrast Transformation on trough TPM concentrations, and one-way ANOVA analyses were performed to evaluate statistical differences between USL255 and TPM IR C_max and C_min TPM concentrations. Results: USL255 achieved SS TPM plasma concentrations sooner than TPM IR (Day 5 vs Day 7, respectively) with no apparent difference in average plasma TPM concentration between formulations. The 90% CI for the AUC_0-24 ratio of the USL255/TPM IR GLSM was completely contained between 0.80 1.25 demonstrating USL255 and twice-daily TPM IR provide equivalent TPM exposure. Similarly, the 90% CIs for both the C_max and C_min ratios were completely contained within the 0.8 1.25 equivalence limits. The time to reach peak exposure at SS was longer for USL255 (6 hr) as compared with TPM IR (1 hr). When USL255 and TPM IR mean SS C_max and C_min values were compared by one-way ANOVA, USL255 demonstrated both a significantly lower peak (P<.001) and significantly higher trough concentrations (P<.001). Further, the FI for USL255 was approximately 26% lower than that of TPM IR. Conclusions: These results confirm that USL255 administered once-daily provides an improved PK profile and decreased FI at SS as predicted by modeling analyses. These data suggest USL255 may offer a once-daily alternative to TPM IR that can provide equivalent TPM exposure, achieve SS concentrations sooner, and reduce fluctuation of TPM concentrations.