Armel Stockis

Levetiracetam Intravenous Infusion: A Randomized, Placebo‐controlled Safety and Pharmacokinetic Study

Summary:  Purpose: The primary objective of this placebo‐controlled study was to evaluate the safety and tolerability of levetiracetam (LEV) administered intravenously (IV) at higher doses and/or at a faster infusion rate than proposed. The secondary objective was to assess LEV pharmacokinetics.

Pharmacokinetics and Metabolism of 14C-Brivaracetam, a Novel SV2A Ligand, in Healthy Subjects

This study was designed to investigate the human absorption, disposition, and mass balance of 14C-brivaracetam, a novel high affinity SV2A ligand with potent anticonvulsant activity. Six healthy male subjects received a single p.o. dose of 14C-brivaracetam (150 mg, 82 μCi, or 3.03 MBq). Serial blood and complete urine and feces were collected until 144 h postdose. Expired air samples were obtained until 24 h. Brivaracetam was rapidly absorbed, with Cmax of 4 μg/ml occurring within 1.5 h of dosing. Unchanged brivaracetam amounted to 90% of the total plasma radioactivity, suggesting a modest first-pass effect. Plasma protein binding of radioactivity was low (17.5%). Urinary excretion exceeded 90% after 2 days, and the final mass balance reached 96.8% of the radioactivity in urine and 0.7% in feces. Only 8.6% of the radioactive dose was recovered in urine as unchanged brivaracetam, the remainder being identified as non–cytochrome P450 (P450)- and P450-dependent biotransformation products resulting from hydrolysis of the amide moiety (M9, 34.2%), hydroxylation of the n-propyl side chain (M1b, 15.9%), and a combination of these two pathways leading to the hydroxy acid (M4b, 15.2%). Minor amounts of taurine and glucuronic acid conjugates and other oxidized derivatives were also identified. Brivaracetam is completely absorbed, is weakly bound to plasma proteins, extensively biotransformed through several metabolic pathways, and eliminated renally.

Evaluation of brivaracetam, a novel SV2A ligand, in the photosensitivity model

Objective: To assess the activity of brivaracetam, a novel SV2A ligand, in the photosensitivity model as a proof-of-principle of efficacy in patients with epilepsy. Methods: A subject-blind placebo-controlled study in patients with photosensitive epilepsy was performed to investigate the effect of single-dose brivaracetam (10, 20, 40, or 80 mg) on photosensitive responses. Each patient was exposed to intermittent photic stimulation that evoked a generalized photoparoxysmal EEG response. Individual standard photosensitivity ranges (SPRs) were recorded post-placebo (day −1) and post-brivaracetam until return to baseline (day 1 to 3). Plasma concentrations of brivaracetam and any concomitant antiepileptic drugs were determined. Results: Of the 18 evaluable patients, none achieved SPR abolishment post-placebo, whereas 14 (78%) achieved complete abolishment post-brivaracetam. Decrease in SPR was seen in 8 patients (44%) post-placebo compared to 17 (94%) post-brivaracetam. Duration of response was twice as long post-brivaracetam 80 mg (59.5 hours) compared with lower doses, although the overall effect was not dose-dependent. Time to maximal photosensitive response was dose-related with the shortest time interval observed at the highest dose (0.5 hours post-brivaracetam 80 mg). The area under the effect curve (SPR change from pre-dose vs time) appeared linearly correlated with the area under the plasma concentration curve. Brivaracetam was well tolerated. The most common adverse events were dizziness and somnolence. Conclusions: Our findings show that brivaracetam clearly suppresses generalized photoparoxysmal EEG response. As such, investigations of the antiepileptic properties and tolerability of brivaracetam are warranted in further clinical studies of patients with epilepsy.

Pharmacokinetics of Levetiracetam in Infants and Young Children with Epilepsy

Summary:  Purpose: To assess the single‐dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in infants and young children with epilepsy.

Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study

ObjectiveTo conduct a thorough QT study of levocetirizine, a non-sedating antihistamine, in accordance with International Conference on Harmonisation (ICH) E14 guidance.MethodsThe study was designed as a single-dose, placebo and positive-controlled, four-way crossover, randomised trial in which 52 healthy male and female subjects participated. Levocetirizine (5 and 30 mg) and placebo were administered double-blind, and the positive control, moxifloxacin (400 mg), was open-label. Electrocardiograms (ECGs) were obtained by continuous Holter monitoring at various time points (three per time point) during a 24-h period at baseline and after each treatment. The ECGs were read centrally in a blinded manner. QT intervals were corrected for heart rate using a gender- and study-specific correction (QTcSS) and Fridericia’s correction (QTcF). The largest QTc time-matched and baseline-subtracted difference between each active drug and the placebo (largest ΔΔQTcSS) was derived from a mixed-effect analysis of variance.ResultsThe one-sided 95% upper limits of the largest ΔΔQTcSS for levocetirizine were 5.7 ms (5 mg) and 3.9 ms (30 mg), with mean estimates of 2.9 and 1.1 ms, respectively. Similar results were obtained for the ΔΔQTcF data. Statistically, moxifloxacin significantly lengthened the QTcSS, with a one-sided 95% lower limit of the largest ΔΔQTcSS of 10.5 ms and a mean estimate of 13.4 ms. There was no relationship between the measured ΔQTcSS and the plasma concentration of levocetirizine, whereas a statistically significant linear relationship was observed with the plasma concentration of moxifloxacin [slope estimate 0.004 ms/(ng/mL); 95% confidence interval: 0.003–0.005].ConclusionsOverall, the results of this thorough QT study indicate that the methodology of the trial was valid and sensitive enough to demonstrate the absence of effect of levocetirizine at both therapeutic (5 mg) and supra-therapeutic (30 mg) doses on cardiac repolarisation.

Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action.

Rapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high‐affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivara‐cetam (BRV) for its rate of brain penetration and its onset of action. BRV was compared with levetiracetam (LEV).

Levetiracetam Intravenous Infusion as an Alternative to Oral Dosing in Patients with Partial‐Onset Seizures

Summary:  Purpose: This multicenter, open‐label study evaluated the short‐term tolerability of intravenously (IV)‐infused levetiracetam (LEV; 500–1,500 mg/100 ml, 15 min, b.i.d.) as a substitute for the same oral dose.

Brivaracetam Disposition in Renal Impairment

Brivaracetam is a novel high‐affinity SV2A ligand currently in clinical development for epilepsy. The objective was to characterize its disposition in patients with renal impairment. A single oral dose of 200 mg brivaracetam was administered to 9 patients with severe renal impairment not requiring dialysis (creatinine clearance <15 mL/ min, n = 6; 15–29 mL/min, n = 3) and 9 matched healthy controls. Plasma and urinary concentrations of brivaracetam and 3 pharmacologically inactive metabolites (acid, hydroxy, and hydroxyacid) were determined up to 72 hours postdose, and noncompartmental pharmacokinetic parameters were derived. The Cmax of brivaracetam was unchanged relative to healthy controls, whereas AUC was slightly increased (mean ratio, 1.21; 90% confidence interval, 1.01–1.45). Nonrenal and renal clearances of brivaracetam decreased from 47 and 4.5 to 41 and 1.7 mL/min/1.73 m2. Exposure to the acid, hydroxy, and hydroxyacid metabolites was markedly increased: Cmax by 2.4‐, 2.0‐, and 11.7‐fold and AUC by 3.2‐, 4.1‐, and 21.5‐fold. Renal clearance of these rapidly cleared metabolites was decreased 10‐fold in patients with severe renal impairment. Nonclinical toxicology studies concluded to the absence of safety issues related to the increased levels of metabolites. These observations suggest that dose adjustment of brivaracetam should not be required at any stage of renal dysfunction.

Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy.

Purpose: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy.

Retrospective Population Pharmacokinetic Analysis of Levetiracetam in Children and Adolescents with Epilepsy : Dosing Recommendations

AbstractObjective: To characterize levetiracetam pharmacokinetics, identify significant covariate relationships and identify doses in children that achieve blood concentrations similar to those observed in adults. Methods: Nonlinear mixed-effects modelling was used to analyse pooled data collected from 228 children with epilepsy aged 3 months to 18 years in five trials of adjunctive levetiracetam therapy. Simulations were used to identify dosing regimens achieving levetiracetam steady-state peak and trough plasma concentrations similar to those attained in adults receiving the recommended starting dose for adjunctive therapy (500 mg twice daily). The covariates considered for inclusion in the base model were age, bodyweight, gender, race, body surface area (BSA), body mass index (BMI), creatinine clearance (CLCR), levetiracetam dose, concomitant antiepileptic drug (AED) by category (neutral, enzyme inducer, inhibitor, combination of inducer and inhibitor), and benzodiazepines. Results: A one-compartment model with first-order absorption and elimination best characterized the data. The following significant covariates were identified: (i) age on the absorption rate constant (ka); (ii) bodyweight, dose, CLCR and concomitant enzyme-inducing AED on plasma oral clearance (CL/F); and (iii) bodyweight on the apparent volume of distribution after oral administration (Vd/F). The main explanatory covariates were age on ka, bodyweight on CL/F and Vd/F, and enzyme-inducing AED on CL/F, of which bodyweight was the most influential covariate. Dosing can be carried out with either 10 mg/kg of oral solution twice daily in children weighing <50 kg and a 500-mg tablet twice daily in those weighing >50 kg or, when patients favour a solid formulation, 10 mg/kg of oral solution twice daily in children weighing <20 kg, a 250-mg tablet twice daily in those weighing 20–40 kg, and a 500-mg tablet twice daily in those weighing >40 kg. All of these doses achieved steady-state peak and trough plasma concentrations similar to those observed in adults following the recommended starting dose for adjunctive therapy (500 mg twice daily). Conclusions: The most influential covariate of levetiracetam pharmacokinetics in children is bodyweight. A starting dose of levetiracetam 10 mg/kg twice daily ensures the same exposure in children as does 500 mg twice daily in adults.