Abstracts

Rationale: Establishing pharmacokinetic (PK) and safety characteristics of a new drug, including dose proportionality and maximum tolerated dose (MTD), are important steps in determining the drug's optimal dosing regimen. Upsher-Smith Laboratories, Inc. is developing USL255, a once-daily extended-release formulation of topiramate (TPM) for the treatment of seizures. USL255 (25 - 400 mg) displays dose proportional TPM exposure with maximum peak exposure (C_max) appearing dose proportional at higher doses (100 - 400 mg). The objective of this study was to evaluate single-ascending doses of USL255 over a larger dose range (600 - 1600 mg) to determine single-dose MTD and examine the PK profile in healthy individuals. Methods: In this Phase 1, randomized, placebo-controlled, double-blind, single-center, single-dose, MTD study, healthy subjects were planned for enrollment into 6 separate cohorts of 10 subjects each for up to 60 total subjects. Subjects in each cohort were randomly assigned 1:4 to placebo or a single dose of USL255 (600, 800, 1000, 1200, 1400, or 1600 mg). Vital sign measurements, clinical laboratory tests, ECG results, and adverse events (AEs) were collected and reviewed for 14 days post-dose. If safety and tolerability were demonstrated after dosing, the study would continue to the next ascending dose until all 6 cohorts were completed. However, if USL255 did not meet a priori safety and tolerability criteria, the previous dose would be named MTD and dose escalation would cease. Blood samples were collected for PK assessments up to 14 days after dosing. Evaluation of dose proportionality was determined using a power model approach, and area under the plasma concentration-time curve (AUC) and C_max were considered dose-proportional if the 90% confidence interval (CI) for the ratio of dose-normalized geometric mean values was between 0.8 - 1.25. Deviation from dose linearity was tested using the type I F test (α=.05). Results: Single doses of USL255 were safe and generally well tolerated from 600 - 1200 mg, and no serious or severe AEs were observed. MTD was declared at 1200 mg after a single subject experienced 16 mild-to-moderate treatment-related AEs, 6 of which began within the first 6 hr following a single administration of USL255 1400 mg. Total (AUC_0-inf and AUC_0-t) and peak (C_max) TPM exposures exhibited dose proportionality over the entire 600 - 1400 mg dose range, as the 90% CIs were completely contained within the 0.8 - 1.25 limit. These PK variables were also linear between 600 and 1400 mg. Time to peak exposure (T_max) ranged between 17 and 20 hr, and elimination half life (t_1/2) decreased with increasing doses. Conclusions: USL255 was well tolerated up to 1200 mg, which was named the single-dose MTD after a subject experienced multiple AEs at 1400 mg. Additionally, USL255 exhibited a TPM exposure profile that was both linear and proportional to dose over the entire 600 - 1400 mg range. These data further support the predictable PK and favorable tolerability profile of once-daily USL255 and aid in determining its optimal dosing regimen.