Pharmacokinetics and Metabolism of 14C-Brivaracetam, a Novel SV2A

ABSTRACT: This study was designed to investigate the human absorption, disposition, and mass balance of 1

It pays to promote joint PhD programmes between academia and the private sector

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

Competencies: A new currency for continuing professional development

“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 disposition in mild to severe hepatic impairment.

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

The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men

© 2008 The Authors; Journal compilation © 2008 Blackwell Publishing LtdWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The pharmacokinetic profile, metabolism and proof of concept of a single oral dose of brivaracetam have been reported. • Previous studies have shown that it was well absorbed, had linear kinetics and was well tolerated, and suggested effective doses of 10–80 mg in photoparoxysmal epilepsy. WHAT THIS STUDY ADDS • We now report the pharmacokinetics, pharmacodynamics and tolerability in healthy volunteers after multiple doses. AIMS 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. METHODS 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. RESULTS Brivaracetam was rapidly absorbed (tmax∼2 h) and eliminated (t1/2 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-β-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. CONCLUSIONS 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.Paul Rolan, Maria Laura Sargentini-Maier, Etienne Pigeolet and Armel Stocki

Brivaracetam-induced elevation of carbamazepine epoxide levels: a post-hoc analysis from the clinical development program

To assess the association, if any, between brivaracetam (BRV)-induced elevated carbamazepine-10,11-epoxide (CBZ-E) and toxicity and efficacy in patients with epilepsy. Data were pooled from three double-blind, placebo-controlled, Phase III studies of adjunctive BRV in adults with uncontrolled focal seizures (N01252/NCT00490035, N01253/NCT00464269, N01358/NCT01261325). Treatment-emergent adverse events (TEAEs) of interest (ataxia, diplopia, dizziness, nystagmus, somnolence, accidental overdose or poisoning, and toxicity), discontinuations due to TEAEs, and serious TEAEs (SAEs) were assessed in subgroups who did/did not receive carbamazepine (CBZ) at study entry (CBZ+ and CBZ-). Logistic regression analysis evaluated CBZ-E/CBZ plasma concentrations and TEAEs. SAEs suggestive of CBZ-E toxicity were summarized from the BRV safety database up to a cut-off of October 1, 2014. Percent reduction in focal seizure frequency over placebo was assessed in subgroups of CBZ-E/CBZ ratios. Data from 1558 patients were included in the pooled safety population. Of these, concomitant CBZ was received by 184/459 (40.1%) placebo-treated and 315/803 (39.2%) BRV-treated patients (≥50 mg/day). In BRV-treated patients, study completion rates were similar in the CBZ+ (92.7%) and CBZ- (88.7%) groups; incidence of TEAEs of interest was similar (CBZ+ 24.4%; CBZ- 24.2%), and did not appear affected by CBZ dosage; SAEs and discontinuations due to TEAEs were CBZ+ 1.6%; CBZ- 3.9% and 2.9%; 9.2%, respectively. Likelihood of TEAEs of interest decreased with increasing CBZ-E/CBZ ratio for BRV-treated patients: odds ratio 0.88 (95% confidence intervals 0.74, 1.03; p = 0.112). In the safety database, five SAEs suggestive of CBZ-E toxicity were identified. Efficacy outcomes did not appear to have a consistent pattern across CBZ-E/CBZ ratio subgroups. This post-hoc analysis does not support an association between CBZ-E levels and TEAEs potentially associated with CBZ-E toxicity, or with increases in efficacy. Overall, current evidence does not suggest that BRV dose adjustment is required with concomitant CBZ

Effect of rifampin on the disposition of brivaracetam in human subjects: further insights into brivaracetam hydrolysis.

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 150mg 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 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)