Christian Otoul

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.

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.

Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam

Purpose:  Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage‐dependent manner. The cognitive effects of BRV are uncertain.

Assessment of levetiracetam bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy: Open-label, single-dose, randomized, four-way crossover study in healthy male volunteers

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 drugs 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), AUC₀₋(last), AUC₀₋(∞) 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.

Comparison of plasma and saliva concentrations of levetiracetam following administration orally as a tablet and as a solution in healthy adult volunteers.

OBJECTIVE Concentrations in saliva, as an alternative to concentrations in blood, can be advantageous for the monitoring of antiepileptic agents. This study assesses the relationship between saliva and plasma concentrations of levetiracetam after administration orally as a solution and as a tablet. The possibility that saliva concentrations of the drug are altered by contamination in the buccal cavity was also examined. METHODS 4 healthy male subjects received a single 750 mg oral dose of levetiracetam as a 10% solution and 4 subjects received three 250 mg tablets (750 mg). Levetiracetam concentrations in plasma and saliva were monitored for 24 hours post dose. RESULTS In subjects receiving the levetiracetam solution, maximum saliva concentrations were observed at the first collection point (15 min) after administration and these were 19-74 times higher than corresponding plasma levels. The mean saliva/plasma ratio rapidly decreased thereafter, becoming stable after 4 hours. In subjects receiving tablets, levetiracetam concentration profiles for saliva paralleled the plasma concentration profiles with a fairly constant saliva/plasma concentration ratio throughout the 24-hour sampling period. A significant linear correlation between levetiracetam saliva and plasma concentrations was demonstrated (Pearson r = 0.88; p < 0.001 for tablet (n = 35) and r = 0.87; p < 0.001 for solution at times > or = 4 hours post-dose (n = 20)). The saliva to plasma concentration ratio was 1.11 (95% confidence interval: 0.99 - 1.22) following tablet intake, and 1.55 (95% CI: 1.34 1.77) following oral solution (> or = 4 hours post dose). CONCLUSIONS Using saliva to monitor therapeutic exposure to levetiracetam is feasible beginning 15 minutes after tablet intake but beginning 4 hours after intake of an oral solution.

Pharmacodynamic Consequences of Administration of VLA-4 Antagonist CDP323 to Multiple Sclerosis Subjects: A Randomized, Double-Blind Phase 1/2 Study

Background Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS). Objective Investigate the effect of CDP323, an oral α4-integrin inhibitor, on lymphocyte biomarkers in RMS. Methods Seventy-one RMS subjects aged 18–65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo. Results Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α4-integrin on VCAM-1–binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions. Conclusions CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes. Trial Registration ClinicalTrials.gov NCT00726648.

Clinical pharmacology of levetiracetam for the treatment of epilepsy

Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic–clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug–drug interactions have been explored across large adult and pediatric populations. The exposure–response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.

Relative Bioavailability and Bioequivalence of Brivaracetam 10 mg/mL Oral Solution and 50-mg Film-Coated Tablet

Brivaracetam was recently approved as adjunctive therapy in the treatment of focal (partial-onset) seizures in patients 16 years of age and older with epilepsy. Brivaracetam is a selective, high-affinity ligand for synaptic vesicle protein 2A.1,2 In phase 2 and 3 studies,3–8 brivaracetam has shown efficacy and good tolerability in adult patients with uncontrolled focal seizures. Brivaracetam pharmacokinetics is doseproportional over a range of doses far exceeding the therapeutic doses.9,10 It is completely absorbed orally (96.8% urinary excretion in mass balance study), shows no food effect, binds weakly to plasma proteins (17.5%), has an apparent volume of distribution corresponding to total body water, and has a plasma half-life of approximately 9 hours.9–11 The major metabolic pathway of brivaracetam involves transformation of the amide function into a carboxylic acid by non-CYP-dependent enzyme amidase EC 3.5.1.4, and a second pathway involves CYP2C19-mediated hydroxylation of the propyl side chain.11–13 An oral solution formulation of brivaracetam has been developed to provide an additional treatment option for patients who have difficulty in swallowing tablets. The objective of this study was to assess the relative bioavailability and bioequivalence of brivaracetam oral solution (10 mg/mL) and brivaracetam 50-mg tablet (reference tablet throughout clinical development) after single administration in healthy participants.

Population pharmacokinetic and pharmacodynamic analysis in allergic diseases

In this chapter, we introduce the concepts and methodologies of population analysis as applied to analyzing pharmacokinetic and pharmacodynamic data. One of the key determining characteristics of the population approach is that through it, one seeks not only to characterize deterministic trends in the data, but also to identify and estimate the magnitudes of the important sources of variability within the data. The first section of this chapter provides an introduction to the primary concepts of, and motivation for, population modeling by way of a hypothetical case study. Then, the various methodologies that have been employed throughout the history of population analysis are described in further detail. Of these, the most commonly employed today is nonlinear mixed-effects (NLME) modeling. Finally, notable examples of the application of population PK and PK/PD modeling to treatments for allergies and asthma are discussed. Population PK models have frequently been used to extrapolate exposures to special populations, such as pediatrics, as well as to optimize treatment regimens and trial designs for these populations. Population PK/PD models have most frequently been applied to analyzing and interpreting data from wheal and flare trials, but are also becoming increasingly important in the analysis of PD data from monoclonal antibodies.

90 Safety, efficacy and transcriptional changes following repeated administration of dapirolizumab pegol in patients with systemic lupus erythematosus: results from a phase i study

Background and aims Binding of CD40 ligand (CD40L) to CD40 activates B cells, antigen-presenting cells and platelets. Evidence suggests CD40L blockade might provide an effective treatment for systemic autoimmune disorders, including systemic lupus erythematosus (SLE). We report data from a Phase I double-blind, multiple dose study (NCT01764594) of dapirolizumab pegol (DZP), a PEGylated anti-CD40L Fab’ fragment, in SLE patients. Methods Twenty-four SLE patients were randomised (2:1, stratified by the presence of anti-phospholipid antibodies) to receive DZP (loading dose 30 mg/kg, then 15 mg/kg every 2 weeks for 10 weeks) or placebo. Patients were followed for 18 weeks. Objectives: safety and tolerability of DZP (primary); disease activity measures (BICLA and SRI-4; exploratory). Genes expressed by plasma cells, B cells, other immune cells and transcripts associated with SLE disease activity were analysed by qPCR. Results No serious adverse events (AEs), thromboembolic events or deaths occurred. Most treatment-emergent AEs (TEAEs) were mild or moderate, transient, and resolved without intervention. Nasopharyngitis was the most common TEAE (6 patients in the DZP group; none with placebo). One patient withdrew due to upper respiratory tract infection (DZP group). Of DZP-treated patients evaluable for BICLA and SRI-4, 46% and 42% respectively, responded by Week 12 (vs 14% placebo; Table 1). Rapid and maintained mechanism-related gene expression changes were observed, particularly in plasma cell genes (IgA, IgG, IgJ) from the DZP group. Table 1 Conclusions DZP was well tolerated and demonstrated improvement in clinical measures of disease activity. A Phase II study is evaluating efficacy and safety of DZP in SLE patients (NCT02804763).