USL255 extended-release topiramate: Dose-proportional pharmacokinetics and tolerability in healthy volunteers.

Objective Evaluate the pharmacokinetics ( PK), safety, and tolerability of single doses of once-daily USL255, Qudexy XR (topiramate) extended-release capsules, over a wide dosing range. Methods Two single-dose, phase I studies in healthy adults were used to evaluate the PK profile and maximum tolerated dose ( MTD) of USL255 from 25-1,400 mg. Standard PK parameters assessed included area under the plasma concentration-time curve ( AUC) and maximum plasma concentration (C_max). Dose proportionality, linearity, and intersubject and intrasubject variability (coefficient of variation [% CV]) of AUC and C_max were evaluated. Investigator-reported adverse events ( AEs) were obtained throughout the studies. Results After the initial increase in plasma concentration levels immediately following administration of USL255 25-1,400 mg, plasma topiramate concentration-time profiles were flat up to 24 h after dosing. AUC was dose proportional from 25-1,400 mg, and C_max was dose proportional from 50-1,400 mg; both AUC and C_max were linear across the entire dose range. Low intersubject and intrasubject % CV values were observed for AUC_0−t, AUC_0−∞, and C_max (intersubject % CV: 20.2, 19.6, and 22.4%, respectively; intrasubject % CV of dose-normalized mean values: 10.8, 8.2, and 13.2%, respectively). USL255 was generally safe and well tolerated with MTD established at 1,200 mg. Significance These results demonstrate that USL255 provides consistent plasma topiramate exposure across an extended-dosing interval and predictable plasma topiramate concentrations over a wide dosing range. Overall, the favorable safety profile and consistency of exposure suggest once-daily USL255 can be a useful treatment option for patients with epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]