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.
SUMMARYPurpose: To compare the pharmacokinetics of USL255, a once-daily extended-release (ER) formulation of topiramate (TPM), with Topamax (immediate-release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics. Methods: This randomized, single-center, open-label, cross-over design study had three dosing periods separated by 21 days of washout between treatments. Thirtysix volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax (100 mg) administered 12 h apart. TPM plasma samples were analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetic parameters were calculated by noncompartmental methods. Key Findings: USL255 fasted pharmacokinetic parameters [point estimate (90% confidence interval, CI) compared to Topamax] were: relative bioavailability (F ) 91.2% (84-99%), peak plasma concentration (C max ) USL255/Topamax-ratio 59% (53-65%), time to reach C max (t max ) 19.5 ± 7.2 h, accumulation ratio (R ac ) 3.9 ± 1.2, effective half-life (t 1/2,eff ) 55.7 ± 19.9 h, terminal half-life (t 1/2,z ) 80.2 ± 14.2 h, and peak-occupancy-time (POT) 12.1 ± 4.0 h. Although the F and C max were unaffected by food, R ac and t 1/2,eff increased to 4.9 ± 0.9, and 72.5 ± 15.4 h, respectively. In contrast to t 1/2,z, t 1/2,eff reflects absorption rate; therefore, USL255's t 1/2,eff was significantly longer than Topamax's t 1/2,eff (37.1 ± 6.5 h). Significance: Although bioequivalent to Topamax in extent of absorption, USL255 had a slower absorption rate as reflected in its lower C max and longer t max , larger POT and longer t 1/2,eff , and similar R ac values to that of Topamax (q12 h). This relative flat plasma profile allows for once-daily dosing with diminished fluctuations in TPM plasma levels. In addition, neither USL255's peak nor extent of plasma exposure of TPM was affected by food.
SUMMARYPurpose: Compare the pharmacokinetic (PK) profiles of immediate-and extended-release formulations of topiramate (TPM) in healthy subjects following multiple dosing, and evaluate maintenance of topiramate exposures after switching formulations. Methods: A randomized, open-label, single-center, twoway crossover, multiple-dose study comparing the steady-state PK profile of once-daily extended-release topiramate (USL255) to immediate-release topiramate (TPM-IR) administered twice-daily. The TPM PK profile was evaluated using standard PK parameters (e.g., AUC 0-24 , C max , C min ) as well as less common PK criteria such as fluctuation index (FI), peak occupancy time (POT), and percent coefficient of variation (%CV). In addition, partial AUC (AUC p ) analyses provided comparisons of the AUC profiles over predetermined time intervals between TPM-IR and USL255. Pharmacokinetic equivalence between formulations was defined as containment of the 90% confidence intervals (CIs) of the USL255/TPM-IR geometric least-squares mean (GLSM) ratio within the equivalence limits of 80-125%. The effect of switching between treatments was assessed by evaluating equivalence of PK parameters between the day prior to formulation switch and the day immediately following formulation switch. Maintenance of steady state after switching formulations was also evaluated by comparing the slope between C min values at formulation switch and 24 h postswitch. Tolerability was evaluated through adverse event monitoring, vital sign measurements, and clinical laboratory evaluations. Key Findings: USL255 was well tolerated and provided TPM plasma exposure equivalent to TPM-IR at various time intervals. USL255 also demonstrated a significantly lower C max (p < 0.001) and higher C min (p < 0.001), longer t max , lower %CV, and 26% decreased FI, as compared with TPM-IR. Further, switching between TPM-IR and USL255 did not affect TPM concentrations, including C min , immediately after transitioning and at steady state. Significance: As compared with TPM-IR, USL255 provided equivalent plasma exposure with an extended absorption profile. Therefore, USL255 offers a once-daily alternative to twice-daily TPM-IR, with reduced TPM fluctuations.
SUMMARYObjective: To compare the pharmacokinetics, pharmacodynamics, and tolerability of USL261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (IV) solution administered intranasally (MDZ-inj IN) or intravenously (MDZ-inj IV) in healthy adults. Methods: In this phase 1, five-way crossover, open-label study, 25 healthy adults (aged 18-42 years) were randomly assigned to receive 2.5, 5.0, and 7.5 mg USL261; 2.5 mg MDZ-inj IV; and 5.0 mg MDZ-inj IN. Blood samples were collected for 12 h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded. Results: Increasing USL261 dose corresponded with increases in midazolam area under the concentration time curve (AUC) and maximum observed plasma concentration (C max ), with all doses demonstrating rapid median time to C max (T max ; 10-12 min). USL261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same MDZ-inj IN dose. USL261 was associated with dose-dependent increases in sedation and psychomotor impairment (p < 0.05); however, these effects lasted <4 h and generally did not differ from MDZ-inj IN or MDZ-inj IV at comparable doses. No serious adverse events (SAEs) or deaths were reported, and no treatment-emergent adverse events (TEAEs) led to study discontinuation. Significance: Compared with intranasal delivery of a midazolam formulation intended for IV delivery, USL261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, USL261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity.
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