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We characterised the bioavailability, safety, and tolerability of brivaracetam 100 mg intravenous bolus and 15-min infusion versus oral reference tablet in 24 healthy Japanese participants.In this randomised, open-label, three-period crossover study, participants received three 100 mg single doses of brivaracetam, intravenous bolus, infusion, and oral tablets. Maximum plasma concentration (C

11C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of11C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in11C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution ( VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VTand VND. However, even with these corrections, CS VToverestimated VNDby ∼35–40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.

Objective This trial evaluated the short-term safety and tolerability, steady-state pharmacokinetics, and preliminary efficacy of brivaracetam oral solution in children aged 1 month to

Summary Objective Brivaracetam (BRV) and levetiracetam (LEV) are antiepileptic drugs that bind synaptic vesicle glycoprotein 2A (SV2A). In vitro and in vivo animal studies suggest faster brain penetration and SV2A occupancy (SO) after dosing with BRV than LEV. We evaluated human brain penetration and SO time course of BRV and LEV at therapeutically relevant doses using the SV2A positron emission tomography (PET) tracer 11C‐UCB‐J (EP0074; NCT02602860). Methods Healthy volunteers were recruited into three cohorts. Cohort 1 (n = 4) was examined with PET at baseline and during displacement after intravenous BRV (100 mg) or LEV (1500 mg). Cohort 2 (n = 5) was studied during displacement and 4 hours postdose (BRV 50‐200 mg or LEV 1500 mg). Cohort 3 (n = 4) was examined at baseline and steady state after 4 days of twice‐daily oral dosing of BRV (50‐100 mg) and 4 hours postdose of LEV (250‐600 mg). Half‐time of 11C‐UCB‐J signal change was computed from displacement measurements. Half‐saturation concentrations (IC 50) were determined from calculated SO. Results Observed tracer displacement half‐times were 18 ± 6 minutes for BRV (100 mg, n = 4), 9.7 and 10.1 minutes for BRV (200 mg, n = 2), and 28 ± 6 minutes for LEV (1500 mg, n = 6). Estimated corrected half‐times were 8 minutes shorter. The SO was 66%‐70% for 100 mg intravenous BRV, 84%‐85% for 200 mg intravenous BRV, and 78%‐84% for intravenous 1500 mg LEV. The IC 50 of BRV (0.46 μg/mL) was 8.7‐fold lower than of LEV (4.02 μg/mL). BRV data fitted a single SO versus plasma concentration relationship. Steady state SO for 100 mg BRV was 86%‐87% (peak) and 76%‐82% (trough). Significance BRV achieves high SO more rapidly than LEV when intravenously administered at therapeutic doses. Thus, BRV may have utility in treating acute seizures; further clinical studies are needed for confirmation.

A combined adult and pediatric population pharmacokinetic model including covariate effects was developed; simulations were subsequently performed to guide intravenous pediatric dosing adaptations. Two pharmacokinetic trials with sparse blood sampling were conducted in children with epilepsy and two trials in healthy adults with serial blood sampling. Lacosamide plasma concentration-time data were available from 43 healthy adults (18-45 years of age; body weight 50-101 kg; n = 1735 concentration vs time records), and from 79 children with epilepsy (6 months-17 years of age; body weight 6-76 kg; n = 402 concentration vs time records), with 14, 22, 25 and 18 participants in age groups2 years, 2 to6 years, 6 to12 years and 12 to18 years, respectively. A two-compartment population pharmacokinetic model was developed using nonlinear mixed effects modeling. Plasma clearance was scaled using a fixed allometric exponent on body weight, while central volume of distribution used a freely estimated allometric exponent. The model-based pharmacokinetic predictions suggested that there is no need to adapt the recommendations regarding intravenous infusion durations in children compared with adults.

A pediatric population pharmacokinetic model including covariate effects was developed using data from 2 clinical trials in pediatric patients with epilepsy (SP0847 and SP1047). Lacosamide plasma concentration-time data (n = 402) were available from 79 children with body weights ranging from 6 to 76 kg, and a balanced age distribution (6 months to

Brivaracetam (BRV) is a new high affinity synaptic vesicle protein 2A ligand recently approved for adults with partial-onset seizures. As a support to in vitro metabolism assays, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method coupled to off-line solid phase extraction (SPE) was developed to quantify BRV acid metabolites, that is, BRV-AC (carboxylic derivative derived from BRV hydrolysis) and BRV-OHAC (corresponding to hydroxylated BRV-AC). The method was validated for various incubates (liver and kidney tissue homogenates and blood, all from humans) and applied to in vitro metabolism assays. The analytes were isolated from buffered samples using ISOLUTE C8 96-well SPE plates. Chromatographic separation was achieved on a Waters Atlantis T3 C18 analytical column (2.1 mm × 50 mm, 5 μm) with detection accomplished using a Waters Premier tandem mass spectrometer in positive ion electrospray and multiple reaction monitoring (MRM) mode. The standard curves, which ranged from 1.00 to 200 ng/mL for BRV-AC, BRV-OHAC, were fitted to a 1/x2 weighted linear regression model. The intra-assay precision and inter-assay precision (expressed as coefficient of variation -%CV) were

Brivaracetam is a selective, high-affinity ligand for synaptic vesicle protein 2A, recently approved as adjunctive therapy in the treatment of focal (partial-onset) seizures in patients 16 years of age and older with epilepsy. The goal of the present analysis was to determine if the dose-response of brivaracetam as monotherapy would fall within the range associated with brivaracetam efficacy as adjunctive therapy. An existing brivaracetam population pharmacokinetic model consisting of first-order absorption, single compartment distribution, and first-order elimination components was extended by estimating the clearance changes due to co-administration of 12 widely prescribed AEDs. Data for the population pharmacokinetic analysis originated from three Phase III add-on trials and two terminated Phase III monotherapy trials. An existing population model of daily seizure rate versus brivaracetam daily average concentration was applied to the data from the three add-on trials. Simulations allowed the assessment of the combined impact of covariate effects on both the pharmacokinetics and the pharmacodynamics of brivaracetam, and indicated that in the absence of other AEDs, only marginal changes in the overall dose-response relationship would be expected. This suggests that brivaracetam can be used as monotherapy without dose modifications.

Introduction Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration–effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). Methods The existing adult PK/PD model for brivaracetam was applied to a combined adult–pediatric dataset of levetiracetam. This model was then used to predict the effective oral twice-daily dose of brivaracetam in children aged ≥4 to

Objectives To quantify the relationship between exposure to lacosamide monotherapy and seizure probability, and to simulate the effect of changing the dose regimen. Methods Structural time-to-event models for dropouts (not because of a lack of efficacy) and seizures were developed using data from 883 adult patients newly diagnosed with epilepsy and experiencing focal or generalized tonic–clonic seizures, participating in a trial (SP0993; ClinicalTrials.gov identifier: NCT01243177) comparing the efficacy of lacosamide and carbamazepine controlled-release monotherapy. Lacosamide dropout and seizure models were used for simulating the effect of changing the initial target dose on seizure freedom. Results Repeated time-to-seizure data were described by a Weibull distribution with parameters estimated separately for the first and subsequent seizures. Daily area under the plasma concentration–time curve was related linearly to the log-hazard. Disease severity, expressed as the number of seizures during the 3 months before the trial (baseline), was a strong predictor of seizure probability: patients with 7–50 seizures at baseline had a 2.6-fold (90% confidence interval 2.01–3.31) higher risk of seizures compared with the reference two to six seizures. Simulations suggested that a 400-mg/day, rather than a 200-mg/day initial target dose for patients with seven or more seizures at baseline could potentially result in an additional 8% of seizure-free patients for 6 months at the last evaluated dose level. Patients receiving lacosamide had a slightly lower dropout risk compared with those receiving carbamazepine. Conclusion Baseline disease severity was the most important predictor of seizure probability. Simulations suggest that an initial target dose >200 mg/day could potentially benefit patients with greater disease severity. Electronic supplementary material The online version of this article (doi:10.1007/s40262-017-0530-8) contains supplementary material, which is available to authorized users.

(11)C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of (11)C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in (11)C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution (V(T)) to nondisplaceable uptake in gray matter, V(ND). Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS V(T) and V(ND). However, even with these corrections, CS V(T) overestimated V(ND) by ∼35–40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.

Objective To assess the effect of brivaracetam (BRV) on steady-state plasma concentrations of commonly prescribed antiepileptic drugs (AEDs). Methods Data were pooled from five randomized, double-blind, placebo-controlled efficacy studies (NCT00175929, NCT00175825, NCT00490035, NCT00464269, and NCT01261325) in which adults with refractory epilepsy, and receiving stable doses of 1–2 AEDs, initiated adjunctive treatment with BRV (or placebo) for up to 12 weeks, following a 4–8 week baseline period. Concentrations of carbamazepine, carbamazepine epoxide, clobazam, clonazepam, lacosamide, lamotrigine, levetiracetam, oxcarbazepine (MHD), phenobarbital, phenytoin, pregabalin, topiramate, valproic acid and zonisamide, were measured during baseline and during BRV or placebo evaluation periods. Log-transformed data for patients receiving BRV dosages of 50–200 mg/day (or placebo) were evaluated using repeated measures analysis of covariance. Geometric least-squares means ratios of respective AED concentrations (treatment vs baseline) and their 90% confidence intervals (CIs) were calculated. Relevant interaction of BRV on the respective AED was inferred if CIs were entirely outside of 0.80–1.25 limits. Results Within the population for analysis (n = 1402), relevant interaction was observed for carbamazepine epoxide alone which increased up to 2-fold from baseline due to inhibition of epoxide hydrolase by BRV, and the effect size was not influenced by concomitant valproic acid. Relevant interaction was not observed for other AEDs. Conclusion In adults with focal seizures, adjunctive BRV treatment does not affect plasma concentrations of the evaluated AEDs but increases carbamazepine epoxide metabolite. Carbamazepine dose reduction should be considered if tolerability issues arise.

Objective This Phase I, open-label, dose-escalation study investigated the effects of steady-state brivaracetam on the pharmacokinetics of carbamazepine in patients with epilepsy, with and without valproate co-administration. Valproate and brivaracetam inhibit epoxide hydrolase and increase carbamazepine epoxide levels. Methods Adult patients with epilepsy being chronically treated with carbamazepine alone (n = 9) or with carbamazepine and valproate (n = 9) received brivaracetam during successive 1-week periods at doses of 50 mg, 100 mg, 200 mg, and 100 mg twice daily (bid). Doses of carbamazepine and valproate must have been stable for at least 3 months. Trough plasma concentrations of carbamazepine, carbamazepine epoxide, and diol metabolites were determined on Days 1, 8, 15, 22, and 29, and at the end of study visit (ESV, 2–3 weeks later). Results Eighteen patients with median (range) age of 45 (20–62) years and body weight of 74 (59–124) kg were enrolled and completed the study. In patients treated with carbamazepine alone, brivaracetam dose-dependently increased mean trough levels of carbamazepine epoxide from 1.38 μg/mL on Day 1 pre-dose to 2.16 μg/mL (+57%) on Day 8 (50 mg bid), 2.72 μg/mL (+97%) on Day 15 (100 mg bid), 3.02 μg/mL (+119%) on Day 22 (200 mg bid), 2.67 μg/mL (+94%) on Day 29 (100 mg bid), and 1.22 μg/mL (−12%) at ESV, respectively. In patients on carbamazepine and valproate, carbamazepine epoxide increased from 1.98 μg/mL at baseline to 2.72 μg/mL (+37%), 3.70 μg/mL (+87%), 4.43 μg/mL (+124%), 3.11 μg/mL (+57%), and 1.94 μg/mL (−2%), respectively. There was no trend for change in carbamazepine, carbamazepine diol or valproate levels. Brivaracetam levels increased linearly with dose. Brivaracetam was well tolerated. Conclusions Carbamazepine epoxide plasma concentrations were approximately doubled by brivaracetam 100 or 200 mg bid. Data are consistent with a dose-dependent and reversible inhibition of epoxide hydrolase by brivaracetam. Carbamazepine epoxide was approximately 0.7 μg/mL higher in presence of valproate. There is no need to limit brivaracetam dosing when used concomitantly with carbamazepine.

1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of 14C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease. 2. Six healthy male subjects received a single oral dose of tozadenant (240 mg containing 81.47 KBq of [14C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection. 3. At 4 h, the Cmax of tozadenant was 1.74 μg/mL and AUC(0-t) 35.0 h μg/mL, t1/2 15 h, Vz/F 1.82 L/kg and CL/F 1.40 mL/min/kg. For total [14C] radioactivity, the Cmax was 2.29 μg eq/mL at 5 h post-dose and AUC(0-t) 43.9 h μg eq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC(0-48h). At 312 h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites. 4. The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.

Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam binds with high affinity to synaptic vesicle protein 2A in the brain, which confers its antiseizure activity. Brivaracetam is rapidly absorbed and extensively biotransformed, and exhibits linear and dose-proportional pharmacokinetics at therapeutic doses. Brivaracetam does not interact with most metabolizing enzymes and drug transporters, and therefore does not interfere with drugs that use these metabolic routes. The favorable pharmacokinetic profile of brivaracetam and lack of clinically relevant drug-drug interactions with commonly prescribed AEDs or oral contraceptives allows administration without dose adjustment, and avoids potential untoward events from decreased efficacy of an AED or oral contraceptive due to a drug-drug interaction. Few agents have been reported to affect the pharmacokinetics of brivaracetam. The strong enzyme-inducing AEDs carbamazepine, phenytoin and phenobarbital/primidone have been shown to moderately lower brivaracetam plasma concentrations, with no adjustment of brivaracetam dose needed. Dose adjustment should be considered when brivaracetam is coadministered with the more potent CYP inducer, rifampin. Additionally, caution should be used when adding or ending treatment with the strong enzyme inducer, St. John's wort. In summary, brivaracetam (50-200 mg/day) has a favorable pharmacokinetic profile and is associated with few clinically relevant drug-drug interactions.

This phase I, open-label study investigated the effects of steady-state brivaracetam administration on steady-state pharmacokinetics of carbamazepine, and steady-state carbamazepine administration on single-dose and steady-state pharmacokinetics of brivaracetam, in 14 healthy participants who received brivaracetam 200mg single doses on days 1 and 22, and 200mg twice daily (bid) on days 24-35; and were titrated to carbamazepine 300mg bid on days 4-35. Brivaracetam did not significantly alter carbamazepine area under the plasma concentration-time curve (AUC) over a dosing interval, but resulted in a 2.6-fold increase in carbamazepine-epoxide. Carbamazepine decreased brivaracetam AUC by 29%, while hydroxy-brivaracetam metabolite was increased by 17%. Urinary 6β-hydroxycortisol/cortisol ratio was unchanged by brivaracetam, but was increased 3-fold by carbamazepine. In vitro hydrolysis of carbamazepine-epoxide in human hepatocytes was inhibited by brivaracetam, with an IC50 of 8.2μM. Brivaracetam 200mg bid was predicted to increase carbamazepine-epoxide by 2.3-fold, in close agreement with the observed value. In conclusion, brivaracetam did not modify carbamazepine exposure but increased carbamazepine-epoxide. Carbamazepine modestly decreased brivaracetam exposure and increased oxidative metabolism.

This double-blind, randomized, three-way crossover study explored the potential pharmacokinetic and pharmacodynamic interactions between ethanol and brivaracetam in 18 healthy males, as required for the development of CNS-active drugs. Subjects received (A) ethanol+brivaracetam, (B) ethanol placebo+brivaracetam and (C) ethanol+brivaracetam placebo. Ethanol was infused as a 5.5-hour intravenous clamp with the first 0.5-hour as loading phase to a target level of 0.6 g/L, and brivaracetam was orally administered as a single 200 mg dose. No relevant pharmacokinetic interactions were observed. Co-administration of brivaracetam and ethanol resulted in decreased saccadic peak velocity, smooth pursuit, adaptive tracking and VAS alertness, and increased body sway, saccadic reaction time and VAS score for ethanol effect compared with brivaracetam alone or ethanol alone. Additionally, the immediate word recall scores were generally lower when brivaracetam was co-administered with ethanol, whereas the delayed word test did not show clear additional effects. A post-hoc exploratory analysis for supra-additivity suggested that most pharmacodynamic effects were likely to be additive in nature, except for adaptive tracking, which appeared to be slightly supra-additive. In conclusion, brivaracetam increased ethanol effects on psychomotor function, attention and memory in healthy males. Intake of brivaracetam with alcohol is not recommended.

The anti-epileptic drug levetiracetam is excreted renally. The objective of this trial was to evaluate the pharmacokinetics of levetiracetam in Japanese patients with renal impairment including end-stage renal disease (ESRD) to confirm that existing dosing instructions-based on data from European patients-are appropriate in a Japanese population.This was a nonrandomised, open-label trial. Six participants were allocated to each of five groups (normal renal function, mild, moderate and severe renal impairment and ESRD); 30 participants in total. Participants received a single dose of levetiracetam 500 mg (normal or mild), 250 mg (moderate or severe), or 500 mg followed by 250 mg post-haemodialysis (ESRD). Blood and urine samples were obtained serially for levetiracetam and metabolite determinations. Noncompartmental pharmacokinetic parameters were calculated and steady-state profiles were simulated using the superposition method.In this trial, levetiracetam total clearance decreased proportionally with creatinine clearance: 52, 31, 25, 20 and 11 mL/min/1.73 m(2) in healthy controls and in patients with mild, moderate, severe renal impairment, and ESRD, respectively. Simulated levetiracetam plasma profiles using the recommended dose adjustments were within the range for normal renal function. Overall, results from this trial were consistent with historical European data.These findings confirm that the dosing instructions are appropriate for Japanese patients with renal impairment including ESRD.

Lacosamide (LCM) is a functionalized amino acid specifically developed for use as an antiepileptic drug (AED) and is currently indicated as adjunctive treatment for partial-onset seizures in adults with focal epilepsy (maximum approved dose 400 mg/day). Characterization of the pharmacokinetic profile is an important aspect in the development of LCM. Studies in healthy subjects and in patients with focal epilepsy have established that LCM has several favorable pharmacokinetic characteristics, including rapid absorption and high oral bioavailability not affected by food, linear and dose-proportional pharmacokinetics, low inter- and intraindividual variability, low plasma protein binding, renal elimination, and a low potential for clinically relevant pharmacokinetic drug-drug interactions both with AEDs and other common medications. Studies have demonstrated bioequivalence among the three LCM formulations (oral tablets, oral solution, and solution for intravenous (IV) infusion), allowing direct conversion to or from oral and IV administration without titration. Thus, the favorable and predictable pharmacokinetic profile and bioequivalence of LCM formulations, coupled with the low potential for clinically relevant pharmacokinetic drug-drug interactions, make LCM an easy-to-use adjunctive treatment for the management of patients with focal epilepsy.

“No research without trained researchers” has become the mantra of the EU-funded Innovative Medicines Initiative (IMI) education and training projects. However, it is often hard to determine the type of training required at different stages of a scientist’s career. The situation is further complicated by the constantly changing environment, e.g. the growth of disruptive technologies, societal expectations of biomedical sciences, the greater need for multi-disciplinary collaborations, and conservative or changing regulatory requirements. This article summarises the experience from a series of five EMTRAIN Public Private Partnership PhD workshops that included both scientific and transferrable skill training. This is followed by an example of a recently developed training programme, including a competency profile, for translational research and medicines development; the C-COMEND teaching programme. The emphasis is on competencies as a new currency for continuing professional development. Finally, this paper describes what we consider to be the next steps required by the scientific community to address solutions to the current training challenges so that society can benefit from the innovations that only science can provide.

Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in Phase III clinical development for epilepsy. This study assessed the effect of brivaracetam 400 mg/day on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive (OC) containing 30 µg ethinylestradiol and 150 µg levonorgestrel, in healthy pre-menopausal women. This open-label, single-center, randomized, two-way crossover, multiple oral dose study (N01080) included two consecutive 28-day cycles without (control) or with brivaracetam (test), and a 28-day follow-up. OC was taken on Days 1–21 of every cycle and brivaracetam 200 mg twice daily was administered on Days 1–20 of the test cycle. Ethinylestradiol and levonorgestrel pharmacokinetics were determined on Day 20 and endogenous hormones were measured frequently during both control and test cycles. Overall, 23/24 participants (age: 19–39 years) completed the study. AUC ratio (90% confidence interval) for brivaracetam versus control was 0.73 (0.69, 0.78) for ethinylestradiol and 0.78 (0.72, 0.83) for levonorgestrel, outside pre-defined bioequivalence limits (0.80–1.25). Levels of endogenous hormones were similar and normal during brivaracetam and control cycles. Brivaracetam in combination with OC was well tolerated. Brivaracetam 400 mg/day co-administered with a combination OC in healthy women reduced ethinylestradiol and levonorgestrel plasma levels but did not result in ovulation.

Brivaracetam is a high-affinity synaptic vesicle protein 2A (SV2A) ligand in clinical development for epilepsy. This open-label, single-dose study evaluated brivaracetam disposition in participants with different degrees of hepatic impairment versus matched healthy controls. Twenty-six participants (38-72 years; 19 males and 7 females) with hepatic impairment classified by Child-Pugh score (mild, n = 6; moderate, n = 7; severe, n = 7) or normal hepatic function (n = 6) received a single oral dose of 100 mg brivaracetam. The pharmacokinetics of brivaracetam and its three main metabolites (acid, hydroxy, hydroxyacid) were determined and correlated with impairment severity. Dynamic liver function tests correlated with hepatic impairment severity. The plasma half-life of brivaracetam was 9.8, 14.2, 16.4, and 17.4 hours and the area under the plasma concentration-time curve was 29.7, 44.6, 46.7, and 47.1 µg h/mL in healthy controls and participants with mild, moderate, and severe liver impairment, respectively. Production of the acid metabolite was increased and the hydroxylated metabolites were decreased in participants with hepatic impairment versus healthy controls. Exposure to brivaracetam increased by 50-60% in patients with hepatic impairment, irrespective of severity. The relative importance of biotransformation pathways was altered; cytochrome P450 (CYP)-dependent hydroxylation decreased; CYP-independent acid metabolite formation increased concomitantly.

Levetiracetam given via intravenous administration has been shown to be an effective alternative in adults with epilepsy when oral administration is not feasible. This study was a prospective single-arm, multicenter study to assess tolerability, safety, and pharmacokinetics of intravenous levetiracetam in children with epilepsy. Children with epilepsy ages 1 month to 16 years requiring intravenous levetiracetam were enrolled. Assessments included vital signs, electrocardiogram, hematology, chemistry, plasma concentrations of antiepileptic medications, weight, physical/neurological examinations, and pharmacokinetics. A total of 52 patients were enrolled. Mild to moderate treatment-emergent adverse events occurred in 63%, the most frequent being pyrexia and dry mouth. Most other treatment-emergent adverse events were considered unrelated to intravenous levetiracetam administration. Therefore, intravenous levetiracetam in the acute setting was overall well tolerated in children 1 month to 16 years.

Purpose The aims of the study were to develop a population pharmacokinetic model of orally administered brivaracetam in paediatric patients and to provide dosing suggestions. Methods Analysis included 600 brivaracetam plasma concentrations from a phase 2a study (NCT00422422; N01263) in 96 paediatric patients with epilepsy aged 1 month to 16 years, taking one to three concomitant antiepileptic drugs (AEDs). Pharmacokinetic analysis was performed using non-linear mixed effects modelling, and a stepwise covariate search was used to determine factors influencing brivaracetam clearance. Simulations were performed to investigate dosing regimens. Results The final model consisted of first-order absorption, single compartment distribution and first-order elimination components with allometric scaling of clearance and volume using lean body weight and fixed allometric exponents. Co-administration with phenobarbital or carbamazepine was associated with a 29% (95%CI 17%/39%) and 32% (22%/42%) decrease in exposure, respectively. Co-administration with valproate was associated with an 11% (1%/23%) increase in exposure. Simulations demonstrated that the majority of children were predicted to have an exposure similar to that in adults, using an age-independent dosing regimen of 2.0 mg/kg bid with a maximum of 100 mg bid for body weight >50 kg. Conclusions A paediatric dose adaptation of 2.0 mg/kg twice daily with a maximum of 100 mg twice daily for body weight >50 kg is predicted to ensure steady-state plasma concentrations in the same range as in adult patients receiving 100 mg twice daily (highest recommended dose). Data suggest no need to change brivaracetam dosing when used concomitantly with carbamazepine, phenobarbital or valproate. Electronic supplementary material The online version of this article (doi:10.1007/s00228-017-2230-6) contains supplementary material, which is available to authorized users.

1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of

Summary Objective To determine the bioequivalence of brivaracetam oral tablet formulations (10, 75, and 100 mg) versus 50 mg oral tablet and to compare the bioavailability of brivaracetam 100 mg intravenous (i.v.) bolus versus 50 and 100 mg tablets, in healthy participants. Methods Phase 1, randomized, open-label, five-period crossover study. Participants received five single doses of brivaracetam: 10, 50 (reference), 75, and 100 mg oral tablets; 100 mg, i.v., bolus injection. Pharmacokinetic parameters (maximum plasma concentration [Cmax], area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration [AUCt], area under the plasma concentration-time curve extrapolated to infinity [AUCinf]) were compared using analysis of variance (ANOVA) following dose normalization and logarithmic transformation. Bioavailability comparisons were based on the 90% confidence intervals (CIs) around the geometric least squares mean ratios (test: reference). Results Twenty-five participants were randomized. The 90% CIs around Cmax, AUCt, and AUCinf ratios for brivaracetam 10, 75, and 100 mg tablets versus 50 mg tablet were entirely contained within the bioequivalence limits (0.8000–1.2500). For brivaracetam 100 mg, i.v., bolus, bioequivalence versus 50 and 100 mg tablets was met for AUCt and AUCinf, but Cmax was partly outside the limits (90% CI: 1.1867–1.3863 and 1.1222–1.3136, respectively). Significance Brivaracetam 10, 75, and 100 mg tablets were bioequivalent to the 50 mg tablet. Brivaracetam 100 mg, i.v., bolus had bioavailability similar to that of 50 and 100 mg tablets.

Background: Levetiracetam is a broad-spectrum antiepileptic drug that binds to synaptic vesicle protein SV2A. Levetiracetam is indicated in the adjunctive treatment of partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures. It is also approved in Europe as monotherapy for newly diagnosed partial-onset seizures. A Phase I clinical pharmacology trial was conducted during preregistration clinical development to better understand the regional gastrointestinal (GI) absorption of levetiracetam. Objective: This study evaluated the relative bioavailability of levetiracetam in various regions of the GI tract using a noninvasive, remote-controlled capsule device providing targeted drug delivery, relative to that after oral administration, and explored the drug's absorption characteristics in healthy volunteers. Methods: Pharmacokinetic data were obtained from healthy men aged 18 to 65 years in an open-label, single-dose, randomized, 4-way crossover study. Treatments included levetiracetam 250 mg administered as an immediate-release tablet and capsule delivery of 250 mg drug substance (levetiracetam powder without excipients) to the proximal small bowel, distal small bowel, and ascending colon. The location of the capsule in the GI tract was monitored using γ-scintigraphic imaging. Blood samples for plasma levetiracetam concentration were collected before dosing; at 10, 20, 30, and 45 minutes; and at 1, 1.5, 2, 3, 6, 9, 12, 16, 20, and 24 hours after tablet intake or after capsule activation. Pharmacokinetic parameters C max , T max , AUC 0−last , AUC 0−∞ and t ½ were calculated using noncompartmental methods. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and interviews with the volunteers regarding adverse events. Results: Nine healthy men, 7 whites and 2 Asians, were enrolled (mean [SD] age, 31 [14] years; weight, 77 [5] kg; height, 176 [6] cm). Six volunteers completed all 4 treatments. Seven adverse events (headache [3], lethargy [2], tachycardia [1], and contusion [1]) were reported in 5 volunteers, but only 2 (headache and lethargy) were judged by the investigator to be possibly drug related. The geometric mean (%CV) AUC 0−last values of levetiracetam delivered in the proximal small bowel, distal small bowel, ascending colon, and stomach (oral tablet) were 58.2 (9.3%), 59.6 (8.9%), 51.5 (12.0%), and 59.0 (7.4%) μg · h/mL, respectively. Values for bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the tablet were 98.5% (95% CI, 89.7%–108.2%), 100.8% (95% CI, 91.4%–111.1%), and 87.1% (95% CI, 77.9%–97.5%). Conclusion: After delivery in the proximal small bowel, distal small bowel, or ascending colon, the systemic bioavailability of levetiracetam (AUC), but not C max and T max , appeared comparable to that after oral administration and thus appeared site independent in this small group of healthy fasting men.

The American College of Rheumatology (ACR) 20% preliminary definition of improvement in rheumatoid arthritis (RA) (ACR20) is widely used in clinical trials to assess response to treatment. The objectives of this analysis were to develop an exposure-response model of ACR20 in subjects receiving treatment with certolizumab pegol and to predict clinical outcomes following various treatment schedules. At each visit, subjects were classified as being ACR20 responders or ACR20 nonresponders or as having dropped out. A Markov mixed-effects model was developed to investigate the effects of the drug on the transitions between the three defined states. Increasing certolizumab pegol exposure predicted an increasing probability of becoming a responder and remaining a responder, as well as a reduced probability of dropping out of treatment. Data from simulations of the ACR20 response rate support the use of dosing regimens of 400 mg at weeks 0, 2, and 4 followed by 200 mg every 2 weeks, or an alternative maintenance regimen of 400 mg every 4 weeks.

Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects.Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day(-1) (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days.Brivaracetam was rapidly absorbed (t(max) approximately 2 h) and eliminated (t(1/2) 7-8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5-8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-beta-hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system-related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose-related sedation and decreased alertness that only persisted at 800 mg daily.Brivaracetam was well tolerated by healthy male volunteers at doses of 200-800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality.

The linkage point between kinetics and dynamics of drugs and other foreign chemicals is at the active site of the target. The response is determined within certain limits by the concentration of the substance at the target and its mechanism of action. However, the concentration of the substance at the active site under in vivo conditions cannot be easily measured, and surrogates such as plasma concentration are used instead. The emergence of in vitro approaches to study some primary pharmacokinetic (PK) and pharmacodynamic (PD) processes in simpler experimental setups could provide ways to estimate the concentration at the active site, which then can be used in a more reliable extrapolation and prediction of in vivo behavior and action of the substance. Imaging and other novel analytical techniques are providing direct or indirect measurements of in vivo concentrations in tissues. In this review, processes such as transport, metabolism, etc. affecting the concentration of the substance at the active site are discussed, analytical possibilities to measure directly or estimate indirectly the concentration at the active site are illustrated, the overall design and performance of physiologically based PK-PD models are described, and some examples concerning blood-brain barrier, liver, and lungs are presented. In conclusion, several important recommendations are made: (1) In vitro systems should be characterized in a much more detailed way than has been done so far, especially with respect to unbound concentrations at the sites of disposition and action; (2) kinetics of the compound in the in vitro system have to be more thoroughly characterized; (3) local models encompassing the in vitro system should be developed and used; and (4) PBPK/PD models should incorporate these local models.

Brivaracetam is a selective high-affinity ligand for synaptic vesicle protein 2A, recently approved as adjunctive therapy in the treatment of partial-onset (focal) seizures in patients 16 years of age and older with epilepsy. A population pharmacokinetic (PK) model and a population pharmacokinetic/pharmacodynamic (PKPD) model were developed describing brivaracetam plasma concentration and the relationship with daily seizure counts in adequate well-controlled efficacy trials. The effect of body weight on clearance and volume was implemented using allometric scaling, and a range of covariates were investigated for their influence on brivaracetam clearance. The PKPD model described daily seizure counts using a negative binomial distribution, taking previous day seizures into account, and using a mixture model to separate "placebo-like" and "response" subpopulations. The PK and PKPD models provided a good description of the data, documented using visual predictive checks. Coadministration with carbamazepine, phenytoin, and phenobarbital decreased brivaracetam exposure by 26%, 21%, and 19%, respectively, without significant effects on PD response. Covariate analysis indicated that levetiracetam coadministration reduced the fraction of subjects in the mixture model response population to 4% and identified baseline seizure frequency as a strong predictor for being assigned to the mixture model response population. Simulation allowed characterization of the dose-response curve, suggesting maximum response is obtained at brivaracetam 150-200 mg/day.

Summary Purpose: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. Methods: The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). Results: The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 μg/ml versus 8.1 μg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 μg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 μg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 μg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. Conclusions: LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.

This study was designed to investigate the human absorption, disposition, and mass balance of (14)C-brivaracetam, a novel high affinity SV2A ligand with potent anticonvulsant activity. Six healthy male subjects received a single p.o. dose of (14)C-brivaracetam (150 mg, 82 microCi, 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 C(max) of 4 mug/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.

To conduct a thorough QT study of levocetirizine, a non-sedating antihistamine, in accordance with International Conference on Harmonisation (ICH) E14 guidance.The 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 delta delta QTcSS) was derived from a mixed-effect analysis of variance.The one-sided 95% upper limits of the largest delta delta QTcSS 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 delta delta QTcF data. Statistically, moxifloxacin significantly lengthened the QTcSS, with a one-sided 95% lower limit of the largest delta delta QTcSS of 10.5 ms and a mean estimate of 13.4 ms. There was no relationship between the measured delta QTcSS 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].Overall, 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.

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.

Summary Purpose To develop a pharmacokinetic model for intravenous levetiracetam in children, based on adult intravenous data and pediatric oral data. Methods Data from two adult Phase-I studies in which levetiracetam was given intravenously were utilized to develop the adult population pharmacokinetic two-compartment intravenous model. After model qualification, combination with an existing pediatric one-compartment oral population pharmacokinetic model enabled simulation of twice-daily intravenous infusions of levetiracetam in children. Median and 90% confidence intervals for C trough , C max (end of infusion) and AUCτ were simulated for 2000 children and compared to the values observed in adults. Results The population pharmacokinetic two-compartment model successfully described intravenous levetiracetam pharmacokinetics in healthy adults. After combination with the oral pediatric population model, steady-state concentrations at the end of 15-, 30- and 60min b.i.d. levetiracetam intravenous infusions in children were predicted to be 29–41, 17–24 and 6–13% higher than those observed after oral dosing of 30mg/kg b.i.d. Concentrations returned to the range of oral exposures within 1h after the infusion peak. The combined model predicted that steady-state peak plasma concentrations and AUCτ in children receiving 30mg/kg twice daily as 15min intravenous infusions were within the range of predicted and observed C max,ss and AUCτ values of adults receiving 15min intravenous infusions of 1500mg levetiracetam. Conclusions The simulations suggest that levetiracetam may be administered intravenously in children as 15min infusions.

Summary Purpose To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response. Methods Design was an open-label, multicenter study. Twenty-one children (4–12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20mg/(kgday) and titrated at 2-week intervals to 40 and then 60mg/(kgday). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale. Results Levetiracetam was rapidly absorbed following oral dosing, with median t max of 0.5h. Dose proportional increases were observed for C max and AUC (0–12) over the dose range; t 1/2 was 4.9h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7–13% faster and AUC was decreased by only 15–24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population ( n =21) and in 56% of those with seizures at baseline ( n =16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated. Conclusion Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy.

In this post hoc analysis, individual seizure counts from four double-blind trials of adjunctive treatment with levetiracetam were analyzed by non-linear mixed-effects modeling (NONMEM). First, a model was fitted to the individual count data assuming a Poisson distribution, in order to classify the patients as either improving or deteriorating from baseline. In the second stage, the dose-response relationship in improving patients was determined by fitting the data to an E(max) model including a placebo effect. The percentage of improvers was 59% on placebo and 73%, 74%, 77% and 73% on levetiracetam 1, 2, 3 and 4g/day, respectively. The ED(50) of 1408mg/day was close to the current WHO Defined Daily Dose of levetiracetam (1500mg). The maximum recommended dose of 3000mg/day was predicted to reduce seizures by >or=90% in 10% of improving patients. Age, gender, body weight, race, and number of concomitant antiepileptic drugs neither affected the percentage of responders nor the extent of change in seizure frequency from baseline.

Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A ligand developed for the treatment of uncontrolled partial-onset seizures. The present phase I, open-label, two-way crossover study was designed to assess the effect of rifampin on the pharmacokinetics of BRV and its hydroxy (BRV-OH), acid (BRV-AC), and hydroxy acid (BRV-OHAC) metabolites. Twenty-six healthy subjects received BRV (150-mg single oral dose) either alone or following 5 days of rifampin 600 mg/day. BRV and its metabolites were examined for their plasma profiles and urinary excretion. Pharmacokinetic modeling was developed to estimate the rate constants of the various metabolic routes. Parallel in vitro assays were conducted to characterize the hydrolysis of BRV to BRV-AC as well as to identify any potential effect of rifampin on the hydrolysis reaction. Rifampin did not significantly affect the maximum plasma concentration (Cmax) of BRV, but decreased its area under the curve (AUC) by 45%. In addition, rifampin significantly increased the AUC of BRV-OH (+109%), decreased the AUC of BRV-AC (-53%), but had little effect on BRV-OHAC (-10%). In vitro assays showed that the major urinary metabolite BRV-AC (33% of the dose) was likely to be formed by amidase EC 3.5.1.4. In vitro data indicated that the enzyme was not significantly inhibited nor induced by rifampin. Modeling confirmed that all of the observed changes in vivo were secondary to the induction of the CYP2C19-mediated hydroxylation of BRV to BRV-OH (3.7-fold increase in the rate constant).

SummaryObjective 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). Methods In vitro permeation studies were performed using Caco-2 cells. Plasma and brain levels were measured over time after single oral dosing to audiogenic mice and were correlated with anticonvulsant activity. Tissue distribution was investigated after single dosing to rat (BRV and LEV) and dog (LEV only). Positron emission tomography (PET) displacement studies were performed in rhesus monkeys using the SV2A PET tracer [11C]UCB-J. The time course of PET tracer displacement was measured following single intravenous (IV) dosing with LEV or BRV. Rodent distribution data and physiologically based pharmacokinetic (PBPK) modeling were used to compute blood–brain barrier permeability (permeability surface area product, PS) values and then predict brain kinetics in man. Results In rodents, BRV consistently showed a faster entry into the brain than LEV; this correlated with a faster onset of action against seizures in audiogenic susceptible mice. The higher permeability of BRV was also demonstrated in human cells in vitro. PBPK modeling predicted that, following IV dosing to human subjects, BRV might distribute to the brain within a few minutes compared with approximately 1 h for LEV (PS of 0.315 and 0.015 ml/min/g for BRV and LEV, respectively). These data were supported by a nonhuman primate PET study showing faster SV2A occupancy by BRV compared with LEV. Significance These preclinical data demonstrate that BRV has rapid brain entry and fast brain SV2A occupancy, consistent with the fast onset of action in the audiogenic seizure mice assay. The potential benefit of BRV for treatment of acute seizures remains to be confirmed in clinical studies.

Levetiracetam is available in China as adjunctive oral therapy for partial-onset seizures. This study was conducted to evaluate the bioequivalence between single-dose intravenous infusion and oral levetiracetam 1500 mg (Part A), and to assess the pharmacokinetics of multiple-dose intravenous infusion at the same dose (Part B) in healthy Chinese subjects. Part A was an open-label, crossover comparison (intravenous vs. oral), while Part B was a double-blind, parallel-group study of intravenous levetiracetam versus intravenous placebo administered for 5 days. Bioequivalence was demonstrated between the 45-min intravenous infusion and oral tablets, with geometric mean area under the plasma concentration–time curve (AUC) from time 0 to infinity (AUC∞) 492.3 and 506.8 μg⋅h/mL, and geometric mean maximum concentration (C max) 65.12 and 55.93 μg/mL for intravenous infusion and oral dosing, respectively. Linear pharmacokinetics were demonstrated (geometric least-squares mean AUC during the dosing interval τ at steady state (AUC τ,ss) 475.6 μg⋅h/mL; geometric least-squares mean AUC∞ after single dose 501.7 μg⋅h/mL; linearity factor = 0.948). Geometric mean C max (77.44 μg/mL) and AUC τ,ss (475.6 μg⋅h/mL) of intravenous infusion levetiracetam 1500 mg after multiple doses were within the expected range, based on their respective single-dose values and the terminal half-life of levetiracetam after a single dose (7.13 h). A theoretical accumulation of approximately 40 % would be expected after multiple doses, which is consistent with the calculated accumulation of 18.0 and 43.5 % (R max and R AUC, respectively). Intravenous infusion of levetiracetam is bioequivalent to oral levetiracetam in healthy Chinese subjects and is a suitable alternative for levetiracetam administration in patients who are temporarily unable to take their medication orally.

Background : Antiepileptic drugs are usually administere dorally, but alternative routes of drug delivery may be required when oral administration is not feasible. Objective : The purpose of this study was to evaluate the single-dose bioavailability of an IV formulation of levetiracetam relative to oral tablets and the multiple-dose tolerability and pharmacokinetics of this formulation compared with placebo in healthy subjects. Methods : This study consisted of 2 phases. Subjects entered the first phase, which was a single-dose, randomized, open-label, 2-way crossover bioavailability comparison of a 15-minute IV infusion of levetiracetam 1500 mg and three 500-mg oral tablets. Subjects then entered the second phase, a multiple-dose, randomized, double-blind, placebo-controlled (2:1), parallel-group tolerability and pharmacokinetic study, in which they received 9 successive doses of levetiracetam 1500 mg IV or placebo at 12-hour intervals. Plasma levetiracetam concentrations were determined by gas chromatography with nitrogen-phosphorus detection. The comparison of bioavailability was based on the 90% CIs around the geometric mean ratios for AUC and C max (IV/oral). Results : Eighteen subjects (9 men, 9 women) participated in the study. All subjects were white. Their mean (SD) age was 35.0 (9.3) years, mean weight 73.3 (14.2) kg, and mean body mass index 23.9 (2.5) kg/m 2 . After a single dose, the IV infusion and oral tablet were similar in terms of C max (50.5 and 47.7 μg/mL, respectively) and AUC (392.4 and 427.9 pg · h/mL). The geometric mean IV/oral ratios were 92.2 (90 % CI, 89.0-95.6) for AUC and 103.7 (90% CI, 91.6-117.4) for C max indicating that the IV and oral formulations were bioequivalent. After multiple twice-daily infusions, steady state was reached within 48 hours. Seventeen (94%) of 18 subjects had ≥1 treatment-emergent adverse event after single-dose administration. During the single-dose phase, the incidence of treatment-emergent adverse events was 89% (16/18) for the IV formulation and 72% (13/18) for the oral tablets; during the multiple-dose phase, the incidence of treatment-emergent adverse events was 67% (8/12) in the IV levetiracetam group and 33% (2/6) in the placebo group. The most common adverse events in the single-dose phase were somnolence (61% IV vs 28% oral) and postural dizziness (17% vs 39%, respectively). The most common adverse events with IV levetiracetam in the multiple-dose phase were also somnolence (33% vs 17% placebo) and postural dizziness (25% vs 0% placebo). Conclusions : In these healthy subjects, single doses of levetiracetam 1500 mg administered as a 15-minute IV infusion and as oral tablets were bioequivalent. General and local tolerability during multiple dosing were good. Steady state was reached within 48 hours. Despite the limitations of a study of short duration and small size conducted in healthy subjects, the findings suggest that use of a 15-minute IV infusion of levetiracetam should be further investigated.

Aims To evaluate retrospectively the population pharmacokinetics of cetirizine, a second-generation antihistamine, in children. Methods Data were pooled from six clinical trials, in which cetirizine was administered orally in various formulations and in single and multiple dosage regimens. The population consisted of 112 children (33 female and 79 male) aged 6 months to 12 years. A one-compartment open model with first-order absorption and elimination was fitted to the plasma concentration-time profiles using nonlinear mixed effects modelling with first-order estimation. Results A linear association was found between apparent clearance (CL/F) and age with the former increasing by 0.12 l h−1 per year. The intercept of the relationship was slightly lower for female children (0.59 vs. 0.77 l h−1 in male). The population estimate of CL/F for an average age of 7 years was 1.61 and 1.43 l h−1 for male and female children, respectively. A linear association was found between apparent volume of distribution (V/F) and age with the former increasing by 1.4 l year−1, with an intercept of 4.0 l. The population estimate of V/F for an average age of 7 years was 13.9 l. The magnitudes of interpatient variability were 35.6% for CL/F and 19.7% for V/F. The magnitude of residual variability in cetirizine concentrations was 26.9%. Conclusions Population analysis predicts a linear increase in cetirizine CL/F and V/F with age, with CL/F being slightly lower in female children, relative to males of the same age. However, this gender difference probably has no clinical consequences. Since V/F increased more rapidly with age than CL/F, a nonlinear increase in half-life was seen, from

Objectives Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating metabolites after oral administration of N. The objectives of this phase IB study were to assess the tolerability and to determine the phannacokinetics of T and TG after 7 days of 0.5 g and 1 g b.i.d. dosing of N in healthy volunteer subjects. Methods Sixteen healthy male volunteers were randomly assigned to 1 of 2 treatment groups. In each group, 2 subjects received a placebo and 6 received a single oral dose of 0.5 or 1 g of N followed by 7 days of b.i.d. dosing. Blood samples were collected during the first and last dosing intervals for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded before and during treatment days. Results The 0.5 g b.i.d. dose was well-tolerated with only mild adverse events not differing significantly from the placebo. The 1 g b.i.d. dose was associated with an increased frequency of gastrointestinal side effects, primarily diarrhea and abdominal discomfort. No significant changes were noted in the ECGs, vital signs and laboratory tests. At the 0.5 g b.i.d. dose, the bioavailability of T and TG was only slightly influenced by repeated administration. At the 1 g b.i.d. dose regimen, the extent of bioavailability of both T and TG was increased by 50-70%, indicating significant accumulation. Tmax was not significantly modified. Conclusion Oral administration of 0.5 g of nitazoxanide b.i.d. for 7 days with food in healthy volunteers is well-tolerated and is not associated with any significant accumulation of T or TG. A higher 1 g dose results in an increased frequency of gastrointestinal discomfort and is associated with significant accumulation of T and TG.

Objectives Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating species metabolites after oral administration of N. Bioavailability is substantially increased by food. The objectives of this phase IA study were to assess the tolerability and to determine the pharmacokinetic linearity of T and TG after single oral administration of increasing doses of N with and without food in healthy volunteer subjects. Methods Thirty-two healthy male volunteers were randomly assigned to 1 of 4 treatment groups. In each successive group, 2 subjects received a placebo and 6 received a single oral dose of 1 g, 2 g, 3 g, or 4 g of N, first under fasted conditions and a week later with a standardized breakfast. Blood samples were collected during 24 h for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded. Results Tolerability was good up to the maximum dose of 4 g. Mild, mostly gastrointestinal side effects were observed and their frequency increased significantly with the dose level. No significant changes were noted in the ECGs, vital signs and laboratory tests. Plasma concentrations increased linearly with the dose from 1 - 4 g, although a trend to increased bioavailability was observed at 4 g. Food approximately doubled the concentrations of T and TG irrespective of dose. Peak times and apparent half-lives increased in proportion to the dose. The apparent body clearance for total T (T+TG) at the highest dose was only half that at the low dose. TG was eliminated more slowly than T. Conclusion Nitazoxanide can be safely administered up to 4 g single oral doses, with or without food. The slow elimination of TG and the overproportional concentrations at the highest dose can be accounted for by solubility- or transport-limited elimination mechanisms becoming apparent at the upper dose level.

The prosperity of a country is closely related to its level of education to fuel research and innovation. Doctoral graduates have attained the highest education level and should be the key players in research and innovation. The number of doctoral graduates is increasing rapidly in most/many countries, but is less well correlated to changes in prosperity of a country.The innovative medicines initiative (IMI) was established to help Europe strengthen its position in biomedical research and development. During its planning stage IMI observed large gaps in the scientific interaction between academia and industry in Europe, and that undergraduate students were not realizing the career opportunities within biomedical R&D. A major objective for the education and training section of IMI, the European Medicines Research Training Network (EMTRAIN, http://www.emtrain.eu), has therefore been to work out a framework for public private partnership PhD (PPP-PhD) and to create a cohort of networking, industry-aware scientists.

Lacosamide (LCM) is a functionalized amino acid specifically developed for use as an antiepileptic drug (AED) and is currently indicated as adjunctive treatment for partial-onset seizures in adults with focal epilepsy (maximum approved dose 400 mg/day). Characterization of the pharmacokinetic profile is an important aspect in the development of LCM. Studies in healthy subjects and in patients with focal epilepsy have established that LCM has several favorable pharmacokinetic characteristics, including rapid absorption and high oral bioavailability not affected by food, linear and dose-proportional pharmacokinetics, low inter- and intraindividual variability, low plasma protein binding, renal elimination, and a low potential for clinically relevant pharmacokinetic drug-drug interactions both with AEDs and other common medications. Studies have demonstrated bioequivalence among the three LCM formulations (oral tablets, oral solution, and solution for intravenous (IV) infusion), allowing direct conversion to or from oral and IV administration without titration. Thus, the favorable and predictable pharmacokinetic profile and bioequivalence of LCM formulations, coupled with the low potential for clinically relevant pharmacokinetic drug-drug interactions, make LCM an easy-to-use adjunctive treatment for the management of patients with focal epilepsy.