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

Abstract

ObjectiveEvaluate the pharmacokinetics (PK), safety, and tolerability of single doses of once-daily USL255, Qudexy XR (topiramate) extended-release capsules, over a wide dosing range.MethodsTwo 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 (Cmax). Dose proportionality, linearity, and intersubject and intrasubject variability (coefficient of variation [%CV]) of AUC and Cmax were evaluated. Investigator-reported adverse events (AEs) were obtained throughout the studies.ResultsAfter 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 Cmax was dose proportional from 50–1,400 mg; both AUC and Cmax were linear across the entire dose range. Low intersubject and intrasubject %CV values were observed for AUC0−t, AUC0−∞, and Cmax (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.SignificanceThese 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.

Clinical utility of topiramate extended-release capsules (USL255): Bioequivalence of USL255 sprinkled and intact capsule in healthy adults and an in vitro evaluation of sprinkle delivery via enteral feeding tubes

“…The most common TEAEs in either treatment group were nausea, paresthesia, dizziness, and headache, and all TEAEs were mild or moderate in intensity. These adverse events were not unexpected for topiramate and have been observed in previous studies of USL255, both in healthy participants and in patients with epilepsy [9][10][11]14,17].…”

“…USL255, Qudexy® XR (topiramate) extended-release capsules (Upsher-Smith Laboratories, Maple Grove, MN, U.S.A.), is a once-daily, XR formulation of topiramate-a broad-spectrum, well-established AED-available as 25-mg, 50-mg, 100-mg, 150-mg, and 200-mg capsules. In previous phase 1 studies, USL255 displayed dose proportional pharmacokinetics (PK) [9] and, compared with immediate-release topiramate dosed twice daily, provided equivalent topiramate exposure with a 26% decreased fluctuation index at steady state [10]. A placebocontrolled, randomized, multinational phase 3 study found that USL255 200 mg was efficacious and generally well tolerated in the adjunctive treatment of partial-onset seizures (POS) [11,12].…”

Topiramate Extended-Release Options: A Focus on Efficacy and Safety in Epilepsy and Comorbidities

“…47 Metabolic acidosis and kidney stones were not reported in patients in this study. 33,47,48 In an article that summarized phase I QXR data from 2 studies (25-400 and 600-1400 mg/day), the incidence of nausea in healthy volunteers was 0% in the placebo group; it was 17% (5 of 30) and 12% (5 of 40) for the lower and higher treatment ranges, respectively. Furthermore, there was a dose-dependent incremental reporting of TEAEs (11% for 25 mg, 46% for 400 mg, and 92% in study subjects who received doses of 600-1400 mg).…”

Antiepileptic drugs in development pipeline: A recent update

“…TPM-IR is approved in many countries as an adjunctive treatment for patients with partial-onset seizures or primary generalized tonic–clonic seizures. USL255 is an extended release topiramate (TPM-XR) formulation that was developed to deliver consistent drug release over a 24 h dosing interval [33] . A double-blind, randomized, placebo controlled PREVAIL Phase III clinical study ( Table 1 ) demonstrated that once-daily administration of USL255 is an effective adjunctive therapy for reducing the seizure frequency in patients with refractory partial onset seizures [32] .…”