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This study compared the pharmacokinetic (PK) profile of a new liquid formulation of mepolizumab with the established lyophilized formulation. In this open‐label, parallel‐group, single‐dose study (NCT03014674; GSK ID: 204958), healthy participants were randomized (1:1:1) to receive a single mepolizumab dose (100 mg) administered subcutaneously as liquid in a single‐use prefilled syringe or single‐use prefilled autoinjector, or as a lyophilized formulation. Maximum plasma concentration, area under the plasma concentration–time curve from time zero (predose) to time of last quantifiable concentration (AUC0–t), and AUC from time zero to infinity (AUC0–∞) as well as additional PK parameters, safety assessments, and blood eosinophil count were evaluated. In total, 244 participants received study drug. All PK parameters were similar across the 3 groups; 90% confidence intervals for maximum plasma concentration, AUC0–t, and AUC0–∞ treatment ratios (liquid prefilled syringe or autoinjector vs lyophilized formulation) were within conventional bioequivalence bounds (0.80‐1.25), demonstrating statistical PK comparability. On‐treatment adverse event incidence was 29% to 38%. Mepolizumab liquid formulation administered via prefilled syringe or autoinjector had similar PK properties to the lyophilized formulation, with no safety concerns identified.

Objectives There are no published reports for anti‐interleukin‐5 therapy in children

Aims GSK3511294 is a humanized anti-interleukin (IL)-5 monoclonal antibody (mAb) engineered for extended half-life and improved IL-5 affinity versus other anti-IL-5 mAbs. This study examined its safety, tolerability, pharmacokinetics (PK) and effect on blood eosinophil counts. Methods This was a double-blind, parallel-group, single-ascending-dose, multicenter, Phase 1 study (205722;NCT03287310) in patients with asthma and a blood eosinophil count ≥200 cells μL-1 . Patients were randomized 3:1 within dose cohorts to receive a single subcutaneous dose of GSK3511294 (2, 10, 30, 100 or 300 mg) or placebo and followed for up to 40 weeks to assess safety (primary endpoint), ratio to baseline in blood eosinophil count, plasma PK parameters and frequency/titers of binding antidrug antibodies (all secondary). Results Forty-eight patients received study drug and completed the study. Adverse events (AEs) occurred in 92% of placebo-treated and 81% of GSK3511294-treated patients. There were no AEs leading to study withdrawal or serious AEs; hypersensitivity (one event in one patient) and injection-site reaction (three events in two patients) occurred infrequently. Marked reductions (>48%) in blood eosinophil count were seen from 24 hours post-dose with all GSK3511294 doses but not placebo; suppression was maintained for longer with increasing dose (82% and 83% adjusted reductions vs placebo with 100 and 300 mg, respectively, at Week 26). PK were linear and dose proportional over the dose range; terminal half-life was 38-53 days. Conclusions GSK3511294 was well tolerated, with linear and dose proportional PK, extended half-life and blood eosinophil count reduction, supporting less frequent dosing versus other anti-IL-5 mAbs.

Assessment of efficacy in important subgroups – such as those defined by sex, age, race and region – in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non‐informative prior.

Objective: A liquid mepolizumab formulation in a single-use prefilled syringe (PFS) is under development. We evaluated the usability of mepolizumab self-injected via PFS by patients with severe eosinophilic asthma (SEA), or their caregivers, in clinic and at home. Methods: This open-label, single-arm, Phase IIIa study included patients with SEA, aged ≥12 years, and receiving mepolizumab (100 mg subcutaneously) every 4 weeks for ≥12 weeks prior to screening. Patients with SEA not receiving mepolizumab at screening who met additional criteria were also included. Patients/caregivers self-administered mepolizumab (100 mg subcutaneously) via PFS every 4 weeks for 12 weeks. The first (Week 0) and third (Week 8) dose were observed in clinic; the second dose (Week 4) was unobserved at home. Primary and secondary endpoints were the proportion of patients who successfully self-administered their third and second doses, respectively. Injection success was determined by investigator/site staff. Patient experience, mepolizumab trough concentrations, blood eosinophil counts, and safety were also assessed. Results: Of the 56 patients/caregivers who self-administered ≥1 dose of mepolizumab, 55 completed the study. All patients were reported to have successfully self-administered their third mepolizumab dose in clinic (N = 55, 100%); this was further evidenced by trough concentrations/blood eosinophil counts. Most patients/caregivers found the PFS easy and convenient to use with 75% (n = 42) expressing little/no anxiety about using the device at home. Incidence of on-treatment drug-related adverse events was low (4%); none were fatal. Conclusions: Patients/caregivers successfully self-administered mepolizumab via the PFS both in clinic and at home, with no new safety concerns identified.

Interleukin 5 (IL‐5) and eosinophils are thought to play an important role in the pathology of asthma. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of mepolizumab, a humanized anti‐IL5 IgG1 monoclonal antibody, in development for the treatment of severe eosinophilic asthma. This single‐blind study randomized 35 healthy Japanese male subjects (3:1) to receive either a single mepolizumab intravenous dose (10, 75, 250, or 750 mg) or placebo. Subjects were observed for up to 151 days postdose, depending on the dose administered. Blood samples were collected to measure mepolizumab concentrations, blood eosinophils, IL‐5, and antibodies to mepolizumab. Mepolizumab exhibited dose‐proportional pharmacokinetics. The terminal phase half‐life was 19.7–34.6 days, independent of dose. Higher mepolizumab plasma concentrations were associated with lower blood eosinophil counts. Mepolizumab 75–750 mg reduced blood eosinophils for ≥3 months postdose. Mepolizumab demonstrated a favorable safety profile: of 41 reported adverse events, most were mild in severity and none were serious. No neutralizing antibodies to mepolizumab were detected. Sustained reduction in blood eosinophils after single intravenous mepolizumab doses ≥ 75 mg, along with mepolizumab pharmacokinetics and a favorable tolerability profile in healthy Japanese subjects, provides a solid foundation for future studies with mepolizumab in Japanese patients with asthma.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • IL-13 can recapitulate the key pathological and clinical features of asthma. • Exhaled NO (FeNO) concentrations are elevated under conditions of pulmonary inflammation, including asthma. • Therapies that inhibit signalling by both IL-13 and the functionally redundant cytokine IL-4 have demonstrated reductions in FeNO, although relationship to dose was not reported. WHAT THIS STUDY ADDS • This study provides the first report of the safety and pharmacokinetics of GSK679586, a novel humanized monoclonal antibody that prevents IL-13 from binding its two known receptors. • This is the first report of the effects on FeNO of a therapy targeting IL-13 alone. Inhibition of IL-13 signalling by GSK679586 produces dose- and time-dependent reductions in FeNO in mild intermittent asthmatics. Thus, FeNO appears to be a dose- and time-responsive clinical biomarker of IL-13 inhibition in mild asthma. AIMS IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586. METHODS In this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg−1) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg−1) or placebo. RESULTS GSK679586 displayed approximately linear pharmacokinetics (based on AUC and Cmax) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL-13 concentrations, indicative of GSK679586–IL-13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg−1 doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs. CONCLUSIONS GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half-life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.

Purpose: The purpose of this study was to investigate the safety and tolerability of Zosuquidar.3HCl, a potent inhibitor of P-glycoprotein (Pgp), when administered p.o. alone and in combination with doxorubicin and to determine whether Zosuquidar.3HCl affects doxorubicin pharmacokinetics and inhibits Pgp function in peripheral blood natural killer lymphocytes. Experimental Design: Patients with advanced nonhematological malignancies were eligible for this Phase I trial. Zosuquidar.3HCl and doxorubicin were administered separately during the first cycle of therapy and then administered concurrently. Zosuquidar.3HCl was administered over 4 days, with doses escalated until the occurrence of dose-limiting toxicity. Subsequently, doxorubicin doses were increased from 45 to 75 mg/m 2 . Zosuquidar.3HCl, doxorubicin, and doxorubicinol pharmacokinetics were analyzed, and dual fluorescence cytometry was used to determine the effects of Zosuquidar.3HCl on Pgp function in natural killer cells. Results: A total of 38 patients were treated at nine dose levels. Neurotoxicity was dose-limiting for oral Zosuquidar.3HCl, characterized by cerebellar dysfunction, hallucinations, and palinopsia. The maximum-tolerated dose for oral Zosuquidar.3HCl administered every 12 h for 4 days is 300 mg/m 2 . Zosuquidar.3HCl did not affect doxorubicin myelosuppression or pharmacokinetics, and Zosuquidar.3HCl pharmacokinetics were similar in the absence and presence of doxorubicin. Higher plasma concentrations of Zosuquidar.3HCl were associated with greater Pgp inhibition in natural killer cells. Conclusion: Zosuquidar.3HCl can be coadministered with doxorubicin using a 4-day oral dosing schedule, with little effect on doxorubicin toxicity or pharmacokinetics. Further refinement in Zosuquidar.3HCl dosing and scheduling should be explored to optimize Pgp inhibition while minimizing cerebellar toxicity.

La politique de recherche francaise s’inscrit dans un systeme complexe, compose d’universites, organismes de recherche, grandes ecoles et autres etablissements de type CHU, Fondations, GIP, etc. Au sein de ce dispositif a plusieurs niveaux, l’unite de recherche constitue l’entite de base : le plus souvent sous tutelle mixte, elle peut etre liee a une ou plusieurs universites ou organismes de recherche, travailler au sein d’une federation, d’une alliance et relever d’un ou plusieurs ministeres...

Background: Expression of B cell maturation antigen (BCMA), a cell surface receptor belonging to the tumor necrosis factor receptor superfamily, is restricted to B cells at later stages of differentiation and is requisite for the survival of long lived plasma cells [Darce, 2007; O’Connor, 2004]. BCMA is also expressed on multiple myeloma (MM) cells and at various frequencies on cells from other B cell malignancies. GSK2857916 is a humanized, afucosylated IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monomethyl auristatin-F (MMAF) via a stable, protease resistant maleimidocaproyl linker. Upon binding to BCMA, GSK2857916 is rapidly internalized and active drug is released within the cell. In addition, GSK2857916 exhibits enhanced antibody-dependent cell-mediated cytotoxicity resulting from afucosylation which increases the affinity of the antibody's Fc domain to FCγRIIIa expressed on immune effector cells. The rationale for the investigation of GSK2857916 in MM and other BCMA-positive hematologic malignancies is supported by the restricted pattern of BCMA expression, and by evidence from preclinical studies [Tai, 2015]. Methods: BMA117159 is a Phase I, open-label, study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity in adult patients with relapsed/refractory MM or select, BCMA-expressing hematologic malignancies. Seventeen MM patients have been enrolled as of 26 January 2016 into the ongoing dose escalation phase with the once every 3 weeks intravenous dosing schedule. A continual reassessment method applied to dose limiting toxicity findings guide dose escalation decisions and maximum tolerated dose determination. Expansion cohorts will include patients with MM and other BCMA-expressing hematologic malignancies. Eligible MM patients are required to have undergone stem cell transplant or be considered transplant ineligible, to have received prior treatment with alkylators, proteosome inhibitors and immunomodulators, and to have documented disease progression on or within 60 days of completion of last therapy. Documented BCMA expression is required for patients with other hematologic malignancies. ClinicalTrials.gov identifier: NCT02064387 Study is funded by GlaxoSmithKline Citation Format: Larry D. Anderson, James Cavet, Adam D. Cohen, Yan Y. Degenhardt, Catherine E. Ellis, Fiona Germaschewski, Nikoletta Lendvai, Edward Libby, Joanna Opalinska, Rakesh Popat, Isabelle Pouliquen, Paul G. Richardson, Keith E. Stockerl-Goldstein, Heather J. Sutherland, Suzanne Trudel, Peter M. Voorhees, Jeffrey Wetherington. A phase I study of GSK2857916, a BCMA-directed monoclonal antibody conjugated to microtubule-disrupting agent in patients with relapsed, refractory multiple myeloma and other BCMA-expressing hematologic malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT034.

IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586.In this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg(-1)) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg(-1)) or placebo.GSK679586 displayed approximately linear pharmacokinetics (based on AUC and C(max)) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL-13 concentrations, indicative of GSK679586-IL-13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg(-1) doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs.GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half-life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.

The purpose of this study was to investigate the safety and tolerability of Zosuquidar.3HCl, a potent inhibitor of P-glycoprotein (Pgp), when administered p.o. alone and in combination with doxorubicin and to determine whether Zosuquidar.3HCl affects doxorubicin pharmacokinetics and inhibits Pgp function in peripheral blood natural killer lymphocytes.Patients with advanced nonhematological malignancies were eligible for this Phase I trial. Zosuquidar.3HCl and doxorubicin were administered separately during the first cycle of therapy and then administered concurrently. Zosuquidar.3HCl was administered over 4 days, with doses escalated until the occurrence of dose-limiting toxicity. Subsequently, doxorubicin doses were increased from 45 to 75 mg/m(2). Zosuquidar.3HCl, doxorubicin, and doxorubicinol pharmacokinetics were analyzed, and dual fluorescence cytometry was used to determine the effects of Zosuquidar.3HCl on Pgp function in natural killer cells.A total of 38 patients were treated at nine dose levels. Neurotoxicity was dose-limiting for oral Zosuquidar.3HCl, characterized by cerebellar dysfunction, hallucinations, and palinopsia. The maximum-tolerated dose for oral Zosuquidar.3HCl administered every 12 h for 4 days is 300 mg/m(2). Zosuquidar.3HCl did not affect doxorubicin myelosuppression or pharmacokinetics, and Zosuquidar.3HCl pharmacokinetics were similar in the absence and presence of doxorubicin. Higher plasma concentrations of Zosuquidar.3HCl were associated with greater Pgp inhibition in natural killer cells.Zosuquidar.3HCl can be coadministered with doxorubicin using a 4-day oral dosing schedule, with little effect on doxorubicin toxicity or pharmacokinetics. Further refinement in Zosuquidar.3HCl dosing and scheduling should be explored to optimize Pgp inhibition while minimizing cerebellar toxicity.

After several years of operation in a context of ISO 9001 certification, a perspective of continuous improvement, the specifics of the apprenticeship status of our students and the desire to professionalize the training led the teaching team of the Quality Master to consider its program in a systems approach and to insert a module called personal development. In this last; an educational system based on a sporting practice has been integrated. The object is to promote awareness and develop a number of skills that learners must reuse in their approach and their assimilation of other more theoretical modules. Thirty master 1 students "Analysis and Quality" at the Faculty of Science and Technology of the University Paul Cézanne Aix Marseille III, thus practiced a form of Japanese fencing for 10 hours spread over a week, none of them knew about this activity. The normal behavior of the beginner in combat appears to be "disorderly" and the first successful actions stand out as brief rational facts. The purpose of this system was to rely on the analysis of these rational facts, in particular to address the need to plan actions to achieve an objective (here, touch without being touched). The satisfaction survey conducted at the end of the training and the written work provided by the students show that this goal has been achieved. Students also emphasize the interest of exchanges and cooperation during the exercises but also the usability of the learning achieved in the overall context of their training. One of our perspectives is to continue the surveys to find out when and how these acquired skills are moreover transferred in professional life., Après plusieurs années de fonctionnement dans un contexte de certification ISO 9001, une perspective d'amélioration continue, les spécificités du statut d'apprenti de nos étudiants et la volonté de professionnalisation de la formation ont conduit l'équipe pédagogique du Master Qualité à envisager son programme dans une approche systémique et à y insérer un module dit de développement personnel. Dans ce dernier; un dispositif pédagogique basé sur une pratique sportive, a été intégré. L'objet est de favoriser les prises de conscience et de développer un certain nombre de compétences que les apprenants doivent réutiliser dans leur approche et leur assimilation d'autres modules plus théoriques. Trente étudiants en master 1 "Analyse et Qualité" à la Faculté des Sciences et Techniques de l'Université Paul Cézanne Aix Marseille III, ont ainsi pratiqué une forme d'escrime japonaise pendant 10 heures réparties sur une semaine, aucun d'entre eux ne connaissait cette activité. Le comportement normal du débutant en combat apparaà®t comme "désordonné" et les premiêres actions réussies ressortent comme des faits rationnels brefs. Le but de ce dispositif était de s'appuyer sur l'analyse de ces faits rationnels notamment pour aborder la nécessité de planifier les actions pour atteindre un objectif (ici, toucher sans être touché). L'enquête de satisfaction menée à la fin de la formation et les travaux écrits rendus par les étudiants montrent que ce but est atteint. Les étudiants soulignent de plus l'intérêt des échanges et de la coopération au cours des exercices mais aussi l'utilisabilité des apprentissages réalisés dans le contexte global de leur formation. Une de nos perspectives est de continuer les enquêtes pour connaà®tre quand et comment ces compétences acquises sont de surcroit transférées dans la vie professionnelle.