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.