Annie Clark

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

To 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.

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

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.

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

OBJECTIVE The objectives of these two studies were to determine if beads from extended-release topiramate capsules sprinkled onto soft food are bioequivalent to the intact capsule and if beads from the capsule can be passed through enteral gastrostomy (G-) and jejunostomy (J-) feeding tubes. METHODS Bioequivalence of 200-mg USL255 (Qudexy XR [topiramate] extended-release capsules) sprinkled onto soft food (applesauce) versus the intact capsule was evaluated in a phase 1, randomized, single-dose, crossover study (N=36). Pharmacokinetic evaluations included area under the curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax), and terminal elimination half-life (t1/2). If 90% confidence intervals (CI) of the ratio of geometric least-squares means were between 0.80 and 1.25, AUC and Cmax were considered bioequivalent. In separate in vitro experiments, 100-mg USL255 beads were passed through feeding tubes using gentle syringe pressure to develop a clog-free bead-delivery method. Multiple tube sizes (14- to 18-French [Fr] tubes), dilutions (5 mg/15 mL-25 mg/15 mL), and diluents (deionized water, apple juice, Ketocal, sparkling water) were tested. RESULTS Area under the curve and Cmax for USL255 beads sprinkled onto applesauce were bioequivalent to the intact capsule (GLSM [90% CI]: AUC0-t 1.01 [0.97-1.04], AUC0-∞ 1.02 [0.98-1.05]; Cmax 1.09 [1.03-1.14]). Median Tmax was 4h earlier for USL255 sprinkled versus the intact capsule (10 vs 14 h; p=0.0018), and t1/2 was similar (84 vs 82 h, respectively). In 14-Fr G-tubes, USL255 beads diluted in Ketocal minimized bead clogging versus deionized water. Recovery of USL255 beads diluted in deionized water was nearly 100% in 16-Fr G-, 18-Fr G-, and 18-Fr J-tubes. SIGNIFICANCE For patients with difficulty swallowing pills, USL255 sprinkled onto applesauce offers a useful once-daily option for taking topiramate. USL255 beads were also successfully delivered in vitro through ≥14-Fr G- or J-tubes, with tube clogging minimized by portioning the dose and using glidant diluents for smaller tubes.

Pharmacokinetic–pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers

AIMS The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association (COWA) test in healthy volunteers after administration of an oral and a novel intravenous (IV) formulation of topiramate (TPM). METHODS Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions. RESULTS Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ~100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l(-1) increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions. CONCLUSIONS This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK-PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population.

Pharmacokinetic‐pharmacodynamic modeling of intravenous and oral topiramate and its effect on the symbol digit modalities test in adult healthy volunteers

A sequential pharmacokinetic‐pharmacodynamic (PK‐PD) modeling approach was used to quantify the effects of a single dose of topiramate (100 or 200 mg) on working memory, attention, and psychomotor speed as measured by the Symbol‐Digit Modalities Test (SDMT). Established on data pooled from 3 randomized, crossover studies in healthy subjects (19–55 years of age), using both oral and a novel stable‐labeled intravenous (IV) formulation of topiramate, an inhibitory Emax model was found to characterize the topiramate concentration‐SDMT score relationship well. At the EC50 of 2.85 μg/mL, this topiramate plasma concentration value was estimated to be associated with a 25.5% reduction of SDMT score relative to baseline. Age was an important determinant of the baseline SDMT score, with an estimated decrease of 1.13% in baseline SDMT score with every year of age. Moreover, this approach enabled the quantification of the practice effect observed with repeated administration of the neuropsychological test over shorter testing intervals than have previously been reported in the literature. The finding of a significant effect following a single dose of topiramate in the range widely used to treat migraine and epilepsy needs to be evaluated in a broader patient population undergoing chronic treatment, as the narrow range of resultant concentrations limits the generalizability of the findings.

Long-term safety and sustained efficacy of USL255 (topiramate extended-release capsules) in patients with refractory partial-onset seizures

OBJECTIVE The aim of this study was to evaluate long-term safety, efficacy, and quality of life (QOL) of ≤400-mg/day USL255, Qudexy® XR (topiramate) extended-release capsules, as adjunctive therapy for partial-onset seizures (POS) in adults. METHODS Patients who completed the 11-week double-blind treatment phase of the phase 3 PREVAIL study were eligible to enroll in this 1-year open-label extension (OLE) study (PREVAIL OLE). The primary objective was to evaluate the safety and tolerability of USL255 (including treatment-emergent adverse events [TEAEs]). The secondary objective was to assess seizure frequency in patients (e.g., median percent reduction from baseline in weekly POS frequency, responder rate [proportion of patients with ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in POS frequency], and seizure-free intervals [proportion of patients who were seizure-free for 4, 12, 24, 36, or 48weeks]). Exploratory clinical-status endpoints included the Global Impression of Change (CGI-C) and Quality of Life in Epilepsy-Problems (QOLIE-31-P) questionnaires. Post hoc analyses evaluated neurocognitive TEAE incidences during the first 11 and entire 55weeks of treatment and efficacy by patient age and drug-resistant status. RESULTS Of the 217 patients who completed PREVAIL (USL255, n=103; placebo, n=114), 210 (97%) enrolled in PREVAIL OLE and were included in the ITT population. Across the entire 55-week treatment period, USL255 was generally safe and well tolerated, with low individual neurocognitive TEAE incidences. Seizure reduction was sustained across the year-long study and observed in patient subgroups, including those with highly drug-resistant seizures and those ≥50years of age. Improvements in CGI-C and QOLIE-31-P were also observed. SIGNIFICANCE The results of PREVAIL OLE are consistent with those from PREVAIL and demonstrate that adjunctive treatment with up to 400mg/day of USL255 may be a safe and effective treatment option for a variety of adult patients with refractory POS.

Plasma topiramate concentrations resulting from doses associated with neuroprotection against white matter injury and stroke in two strains of rat pups

Background:Cerebral white matter (WM) injury and stroke are common neuropathological injuries in newborns with congenital heart defects (CHDs) requiring surgery. Previous investigations in Long Evans rat pups subjected to hypoxia–ischemia found that intraperitoneal (i.p.) topiramate (TPM) at 30 mg/kg, but not 50 mg/kg, conferred neuroprotection. In Sprague-Dawley pups, a dose of 30 mg/kg protected against stroke. Concentrations associated with neuroprotective doses were not measured. The aims of this investigation were to determine concentrations associated with neuroprotective doses and to investigate the pharmacokinetics (PK) of i.p. TPM.Methods:Concentration–time data following administration of 30 and 50 mg/kg doses were analyzed using nonlinear mixed–effect modeling.Results:Mean predicted steady-state maximum and average concentrations following 30 mg/kg TPM were 31.3 and 16.8 μg/ml in Long Evans and 39.9 and 24.4 μg/ml in Sprague-Dawley pups. Mean predicted steady-state maximum and average concentrations following 50 mg/kg TPM were 52.1 and 28.1 μg/ml in Long Evans and 66.5 and 40.6 μg/ml in Sprague-Dawley pups. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.0470 ml/min and 22.2 ml, respectively, for Long Evans and 0.0325 ml/min and 19.7 ml, respectively, for Sprague-Dawley pups.Conclusion:TPM concentrations associated with neuroprotective doses were determined. Body size and strain were significant covariates on CL/F and V/F. Results provide targets for future neuroprotection studies.

The application of half-life in clinical decision making: Comparison of the pharmacokinetics of extended-release topiramate (USL255) and immediate-release topiramate

OBJECTIVE For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t1/2eff) may be a more clinically relevant parameter than elimination half-life (t1/2z). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate- and extended-release topiramate (TPM-IR and USL255, respectively) to understand how drug pharmacokinetics may impact drug dosing recommendations. METHODS The t1/2z and t1/2eff for USL255 and TPM-IR were compared using data from a phase I study (N=36) of 200mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t1/2z was investigated. To further explore the relationship between half-life and dosing, steady-state PK was simulated for USL255 and TPM-IR. RESULTS As previously reported, mean t1/2z was similar between USL255 (80.2h) and TPM-IR (82.8h); TPM-IR t1/2z was ∼4 times longer than reported in the Topamax label (21h). In contrast, USL255 displayed a 1.5 fold longer t1/2eff (55.7 vs 37.1h for TPM-IR). When t1/2z was calculated from 48 to 336h, values ranged from 28.8 to 82.8h. Simulated steady-state PK profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID. SIGNIFICANCE As expected for the same moiety, t1/2z of USL255 and TPM-IR were similar; however, the longer t1/2eff for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPM-IR). Further, sampling duration impacted t1/2z, diminishing its predictive value for determining dose regimens; sampling-time differences may also explain t1/2z discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long t1/2z, taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t1/2z may be less clinically meaningful than t1/2eff, and using t1/2z for some drugs may lead to erroneous conclusions regarding dosing regimens.