Abstracts

Rationale: Upsher-Smith Laboratories, Inc. has developed USL255, a once-daily extended-release formulation of topiramate (TPM), for the treatment of epilepsy. As some patients with epilepsy may have difficulty swallowing tablets or capsules, USL255 was formulated to allow for oral delivery by opening the intact capsule and sprinkling its small multiparticulate beads onto soft foods. A primary objective of this study was to confirm pharmacokinetic (PK) equivalence between the USL255 beads sprinkled onto soft food compared with the intact USL255 capsule.Methods: In this phase 1, open-label, single-center, single-dose, crossover study, a total of 36 healthy subjects (aged 18-64 years) were randomized to receive both an intact USL255 200 mg capsule administered under fasting conditions and USL255 200 mg opened and sprinkled onto one tablespoonful of applesauce after an overnight fast; treatment periods were separated with a minimum 3-week washout. Blood samples were collected for 14 days after each dose and standard PK parameters were calculated including area under the plasma concentration-time curve (AUC_0-t and AUC_0- ), maximum plasma concentration (C_max), time to maximum plasma concentration (T_max), and terminal elimination half-life (t_1/2). Pharmacokinetic equivalence between administration methods was evaluated; AUC and C_max values were considered equivalent if the ratio of the geometric least-squares mean (GLSM) values had a 90% confidence interval (CI) between 0.8 1.25. Safety and tolerability were evaluated through the collection of adverse events (AEs), vital sign measurements, ECGs, and clinical laboratory evaluations.Results: Total TPM plasma exposure (AUC) was equivalent between USL255 200 mg administered as an intact capsule and sprinkled onto soft food (GLSM [90% CI]: AUC_0-t, 1.01 [0.97 1.04]; AUC_0- , 1.02 [0.98 1.05]). Additionally, equivalence between the intact capsule and sprinkled beads was established for C_max (GLSM [90% CI], 1.09 [1.03 1.14]), and t_1/2 was similar for both administration methods (81.5 hr intact vs 83.6 hr sprinkled). Median T_max for USL255 was between 10 14 hours. USL255 200 mg was generally well tolerated, with similar types and numbers of AEs reported between both groups. The most commonly reported treatment-emergent AEs were nausea, dizziness, headache, and paraesthesia. One serious adverse event of anemia was reported 15 days after USL255 dosing, but was deemed unrelated to study treatment.Conclusions: USL255, when sprinkled onto soft food, demonstrated pharmacokinetic equivalence for both AUC and C_max when compared with the intact capsule. Therefore, USL255 can be a beneficial treatment option for the management of epilepsy and provides additional value for individuals with difficulty swallowing whole capsules or tablets. Supported by Upsher-Smith Laboratories, Inc.