Abstracts

Rationale: Fluctuations in plasma concentrations of antiepileptic drugs (AEDs) can lead to increased side effects at peak concentrations or break-through seizures at trough concentrations. Compared to immediate-release (IR) formulations, extended-release (ER) AEDs provide more stable serum concentrations with less frequent treatment administration. Upsher-Smith Laboratories, Inc. has developed USL255, a once-daily ER formulation of topiramate (TPM). In single-dose studies, TPM exposure was equivalent between once-daily 200 mg USL255 and 100 mg TPM IR administered every 12 hr. In addition, USL255 also demonstrated an improved pharmacokinetic (PK) profile with lower C_max and higher C_min. The objectives of this study were to evaluate the dose proportionality and tolerability of USL255 at 25, 50, 100, 200, and 400 mg.Methods: This Phase I, single-dose, open-label, 5-way crossover trial involved healthy subjects (N=30) who were randomized to 1 of 5 treatment sequences, with 6 subjects per sequence. Following treatment, subjects entered a 3-week washout period with blood samples collected during the first 14 days. Standard PK parameters were calculated including maximum plasma concentration (C_max), time to peak plasma concentration (T_max), area under the plasma concentration-time curve (AUC_0-t and AUC_0-?), and half-life (t_1/2). Dose proportionality was determined using a power model approach. PK parameters were considered proportional if the confidence interval (CI) for the ratio of dose-normalized geometric mean values (R_dnm) was between 0.8 1.25. Linearity was assessed by modeling, and deviation from linearity was tested using the type I F test (?=.05). Tolerability was evaluated through the collection of adverse events (AEs), vital sign measurements, and clinical laboratory evaluations.Results: Total TPM exposure (AUC_0-t and AUC_0-?) was linear and dose proportional from 25 mg 400 mg of USL255. Maximum plasma concentration increased from 203 ng/mL (25 mg) to 5,790 ng/mL (400 mg), which neared dose-proportionality (R_dnm 90% CI, 1.10 1.27) for the 100 mg 400 mg doses. Subsequent analyses compared the dose-normalized C_max values of USL255 400 mg to 200 mg, and 200 mg to 100 mg. All 90% CIs were contained between 0.80 1.25, indicating that C_max changed proportionally within double dose increases from 100 to 400 mg. Single dose T_max ranged from 16 hrs 23 hrs, and t_1/2 ranged from 71 hrs 95 hrs. All doses of USL255 were well tolerated, and the percentage of subjects who experienced a treatment-emergent AE generally increased with ascending doses.Conclusions: USL255 exhibited a TPM exposure profile that was linear and dose proportional up to 400 mg/day and was generally well tolerated. Maximum peak exposure appeared dose proportional over the higher doses (100 mg 400 mg). Together these data suggest that USL255 may provide a once-daily alternative to TPM IR with flexible dosing over 25 mg 400 mg resulting in predictable plasma concentrations with a favorable tolerability profile.