Comparative steady-state pharmacokinetic evaluation of immediate-release topiramate and USL255, a once-daily extended-release topiramate formulation

Purpose Compare the pharmacokinetic (PK) profiles of immediate- and extended-release formulations of topiramate (TPM) in healthy subjects following multiple dosing, and evaluate maintenance of topiramate exposures after switching formulations. Methods A randomized, open-label, single-center, two-way crossover, multiple-dose study comparing the steady-state PK profile of once-daily extended-release topiramate (USL255) to immediate-release topiramate (TPM-IR) administered twice-daily. The TPM PK profile was evaluated using standard PK parameters (e.g., AUC_0-24, C_max, C _min) as well as less common PK criteria such as fluctuation index (FI), peak occupancy time (POT), and percent coefficient of variation (%CV). In addition, partial AUC (AUC_p) analyses provided comparisons of the AUC profiles over predetermined time intervals between TPM-IR and USL255. Pharmacokinetic equivalence between formulations was defined as containment of the 90% confidence intervals (CIs) of the USL255/TPM-IR geometric least-squares mean (GLSM) ratio within the equivalence limits of 80-125%. The effect of switching between treatments was assessed by evaluating equivalence of PK parameters between the day prior to formulation switch and the day immediately following formulation switch. Maintenance of steady state after switching formulations was also evaluated by comparing the slope between C_min values at formulation switch and 24 h postswitch. Tolerability was evaluated through adverse event monitoring, vital sign measurements, and clinical laboratory evaluations. Key Findings USL255 was well tolerated and provided TPM plasma exposure equivalent to TPM-IR at various time intervals. USL255 also demonstrated a significantly lower C_max (p < 0.001) and higher C_min (p < 0.001), longer t_max, lower %CV, and 26% decreased FI, as compared with TPM-IR. Further, switching between TPM-IR and USL255 did not affect TPM concentrations, including C_min, immediately after transitioning and at steady state. Significance As compared with TPM-IR, USL255 provided equivalent plasma exposure with an extended absorption profile. Therefore, USL255 offers a once-daily alternative to twice-daily TPM-IR, with reduced TPM fluctuations.