Comparative pharmacokinetic analysis of USL255, a new once-daily extended-release formulation of topiramate

Lambrecht, Lawrence J.; Shekh‐Ahmad, Tawfeeq; Todd, Wesley; Halvorsen, Mark; Bialer, Meir

doi:10.1111/j.1528-1167.2011.03183.x

Cited by 21 publications

(35 citation statements)

References 21 publications

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“…As confirmation of our result, a similarly long half‐life has been reported by Lambrecht et al. (). It now appears that TPM has a much longer half‐life than previously reported, which may permit less frequent daily dosing than is current practice.…”

Section: Discussionsupporting

confidence: 94%

Intravenous topiramate: Comparison of pharmacokinetics and safety with the oral formulation in healthy volunteers

et al. 2013

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SUMMARYPurpose: Although oral topiramate (TPM) products are widely prescribed for migraines and epilepsy, injectable TPM is not available for human use. We have developed a solubilized TPM formulation using a cyclodextrin matrix, Captisol with the long-term goal of evaluating its safety and efficacy in neonatal seizures. This study in healthy adult volunteers was performed as required by the U.S. Food and Drug Administration (FDA) to demonstrate the pharmacokinetics and safety prior to initiation of studies involving children. This study allowed investigation of absolute bioavailability, absolute clearance, and distribution volume of TPM, information that could not be obtained without using an intravenous TPM formulation. Methods: This study was an open-label, two-way crossover of oral and intravenous TPM in 12 healthy adult volunteers. Initially two subjects received 50 mg, intravenously and orally. Following evidence of safety in the first two subjects, 10 individuals received 100 mg doses of intravenous and oral TPM randomly sequenced 2 weeks apart. Blood samples were taken just prior to drug administration and at intervals up to 120 h afterwards. TPM was measured using a validated liquid chromatography-mass spectrometry method. Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2.Key Findings: All subjects completed the study. The mean (AEstandard deviation) absolute oral bioavailability was 109% (AE10.8%). For intravenous and oral TPM the mean distribution volumes were 1.06 L/kg (AE0.29) and 0.94 L/ kg (AE0.24). Clearances were 1.33 L/h (AE0.26) and 1.22 L/h (AE0.26). The half-life values were 42.3 h (AE6.2) and 41.2 h (AE7.5). No changes in heart rate, blood pressure, electrocardiography, or infusion site reactions were observed. Mild central nervous system cognitive adverse events and ataxia occurred between dosing and 2 h post dose with both intravenous and oral administration. With intravenous TPM, these adverse effects occurred as early as during the 15-min intravenous infusion. Significance: In healthy adults, oral TPM is bioequivalent to intravenous TPM, and infusion of 50-100 mg over 15 min is safe. Neurologic effects occurred during the infusion, demonstrating that TPM rapidly diffuses into the brain, which supports its evaluation for neonatal seizures. Results from this pilot study will inform the design of subsequent studies in children and newborns, including controlled clinical trials intended to assess the efficacy and safety of intravenous TPM for neonatal seizures. In addition, our results provide support for the further development of intravenous TPM as bridge therapy for older children and adults in whom oral TPM therapy is interrupted.

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Section: Discussionsupporting

confidence: 94%

Intravenous topiramate: Comparison of pharmacokinetics and safety with the oral formulation in healthy volunteers

et al. 2013

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“…USL255 is a proprietary multiparticulate (beads in a capsule) formulation recently approved by the U.S. Food and Drug Administration (FDA; 11 March 2014) as initial monotherapy in patients ≥10 years of age with partial‐onset seizures (POS) or primary generalized tonic–clonic (PGTC) seizures and adjunctive therapy in patients ≥2 years of age with POS, PGTC, or seizures associated with Lennox‐Gastaut syndrome . In previous phase I studies, USL255 displayed equivalent drug exposure to TPM‐IR, with a smoother concentration‐time curve and an improved steady‐state PK profile (e.g., reduced fluctuation index, significantly decreased maximum plasma concentrations) . In addition, switching between topiramate formulations did not affect steady‐state exposure, including minimum plasma topiramate concentrations, suggesting that at equivalent total daily doses, USL255 will maintain topiramate concentrations at or above the minimum concentrations provided by TPM‐IR .…”

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confidence: 79%

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

et al. 2014

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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.

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“…USL255, Qudexy XR (topiramate) extended‐release capsules (Upsher‐Smith, Maple Grove, MN, U.S.A.), is a proprietary once‐daily XR topiramate formulation that was developed using a coated‐bead technology to deliver consistent drug release over a 24 h dosing interval . USL255 provides plasma topiramate exposure equivalent to TPM‐IR with a significantly lower maximum concentration (C max ) and higher minimum concentration (C min ), leading to decreased fluctuations in drug plasma concentrations . In addition, USL255 maintains the therapeutic minimum topiramate concentrations achieved by TPM‐IR following a formulation switch .…”

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confidence: 99%

Once‐daily USL255 as adjunctive treatment of partial‐onset seizures: Randomized phase III study

et al. 2014

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ObjectiveTo evaluate the efficacy and safety of USL255, Qudexy™ XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs.MethodsIn this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated.ResultsAcross the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life.SignificanceThe PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects.

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Comparative pharmacokinetic analysis of USL255, a new once-daily extended-release formulation of topiramate

Cited by 21 publications

References 21 publications

Intravenous topiramate: Comparison of pharmacokinetics and safety with the oral formulation in healthy volunteers

Intravenous topiramate: Comparison of pharmacokinetics and safety with the oral formulation in healthy volunteers

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

Once‐daily USL255 as adjunctive treatment of partial‐onset seizures: Randomized phase III study

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