Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize ...lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics.
Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s FEV1, and fractional exhaled nitric oxide FeNO) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline.
Lebrikizumab PK was described by a two-compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day−1 for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half-life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV1 and FeNO showed increased response at higher exposure quartiles, while flat or unclear exposure-response relationships were observed in exacerbation rate.
Lebrikizumab PK is as expected for a typical immunoglobulin G4 monoclonal antibody. Results from the exposure-response analyses suggested that, compared to 125 mg Q4W, the 37.5 mg Q4W dose did not achieve the maximum responses for FEV1 and FeNO, although it appeared to maximize the effect on exacerbation reduction. This suggests that the antibody levels needed to improve these outcomes may not be the same. In addition, the role of IL-13 in airflow obstruction/airway inflammation and asthma exacerbations might be different and targeting multiple pathways may be required to treat this heterogeneous disease and provide clinically meaningful benefits to asthma patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Teamwork is essential for health care providers, who must work together to ensure safe and effective patient care. The ability to function effectively as a team is especially important in critical ...care, where ad hoc teams are brought together for short-term management of crisis situations. Teamwork training has been widely implemented, but ongoing education and practice are needed to maintain and improve competency. This article reviews some of the literature on team science and provides recommendations for enhancing training to promote development of a shared mental model. Strategies such as ensuring multidisciplinary participation, clarifying team resources and goals, and creating practice scenarios can increase the effectiveness of training for critical care teams. Evaluation can provide immediate feedback on learning outcomes and may facilitate subsequent transfer of learning to the clinical setting. Interventions that improve a team's ability to work toward a common goal can improve outcomes for critically ill patients.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Summary
Background
Vedolizumab, an anti‐α4β7 integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease ...(CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing.
Aims
To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic–pharmacodynamic relationship using population modelling.
Methods
Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data.
Results
Vedolizumab pharmacokinetics was described by a 2‐compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half‐life of vedolizumab was 25.5 days; linear clearance (CLL) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (Vc) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for Vc; residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CLL.
Conclusions
Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Prospectively designed studies assessing the exposure‐response profile of vedolizumab are lacking. Observational exposure‐response data for vedolizumab are limited and have not ...been adjusted for potential confounding factors, particularly those that may affect vedolizumab clearance.
Aims
To (a) investigate the vedolizumab exposure‐response relationship after adjusting for potential confounding variables; (b) propose potential target serum vedolizumab concentrations for future study; (c) ascertain whether early vedolizumab serum concentrations were associated with short‐ and long‐term clinical outcomes in adults with ulcerative colitis in GEMINI 1.
Methods
Propensity‐score‐based case‐matching analysis was performed using data from GEMINI 1 and an earlier large population pharmacokinetic study, with vedolizumab clearance or concentration as predictors of clinical remission and response, adjusted for age, weight, anti‐tumour necrosis factor alpha therapy history, serum albumin and faecal calprotectin concentrations. Potential vedolizumab concentration targets at weeks 6, 14 and steady state were proposed. Association between early vedolizumab concentrations at weeks 2, 4 and 6 and clinical remission at weeks 14 and 52 was evaluated.
Results
Among 693 patients with pharmacokinetic data at week 6, potential target vedolizumab concentrations at weeks 6, 14 and steady state were 37.1, 18.4 and 12.7 µg/mL respectively. Week 6 was identified as the earliest time at which vedolizumab concentrations were consistently associated with clinical remission at weeks 14 and 52.
Conclusions
In this comprehensively adjusted analysis, vedolizumab concentrations at week 6 were associated with short‐ and long‐term remission. Potential induction and maintenance target concentrations were proposed for further study.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
This historical review summarizes the major advances – particularly from the last 50 years – in transcutaneous motor-level electrical stimulation, which can be used either as a tool to investigate ...neuromuscular function and its determinants (electrical stimulation for testing; EST) or as a therapeutic/training modality to improve neuromuscular and physical function (neuromuscular electrical stimulation; NMES). We focus on some of the most important applications of electrical stimulation in research and clinical settings, such as the investigation of acute changes, chronic adaptations and pathological alterations of neuromuscular function with EST, as well as the enhancement, preservation and restoration of muscle strength and mass with NMES treatment programs in various populations. For both EST and NMES, several major advances converge around understanding and optimizing motor unit recruitment during electrically-evoked contractions, also taking into account the influence of stimulation site (e.g., muscle belly vs nerve trunk) and type (e.g., pulse duration, frequency, and intensity). This information is equally important both in the context of mechanistic research of neuromuscular function as well as for clinicians who believe that improvements in neuromuscular function are required to provide health-related benefits to their patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis UC or Crohn's disease CD has been reported. Here we further explore ...exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data.
Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 Caverage as exposure measure.
Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml 5th and 95th percentiles, respectively. On average, patients with higher albumin, lower faecal calprotectin UC only, lower C-reactive protein CD only, and no previous tumour necrosis factor-α TNFα antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients.
Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation.
Mycoprotein is a fungal-derived sustainable protein-rich food source, and its ingestion results in systemic amino acid and leucine concentrations similar to that following milk protein ingestion.
We ...assessed the mixed skeletal muscle protein synthetic response to the ingestion of a single bolus of mycoprotein compared with a leucine-matched bolus of milk protein, in rested and exercised muscle of resistance-trained young men.
Twenty resistance-trained healthy young males (age: 22 ± 1 y, body mass: 82 ± 2 kg, BMI: 25 ± 1 kg·m−2) took part in a randomized, double-blind, parallel-group study. Participants received primed, continuous infusions of L-ring-2H5phenylalanine and ingested either 31 g (26.2 g protein: 2.5 g leucine) milk protein (MILK) or 70 g (31.5 g protein: 2.5 g leucine) mycoprotein (MYCO) following a bout of unilateral resistance-type exercise (contralateral leg acting as resting control). Blood and m. vastus lateralis muscle samples were collected before exercise and protein ingestion, and following a 4-h postprandial period to assess mixed muscle fractional protein synthetic rates (FSRs) and myocellular signaling in response to the protein beverages in resting and exercised muscle.
Mixed muscle FSRs increased following MILK ingestion (from 0.036 ± 0.008 to 0.052 ± 0.006%·h−1 in rested, and 0.035 ± 0.008 to 0.056 ± 0.005%·h−1 in exercised muscle; P <0.01) but to a greater extent following MYCO ingestion (from 0.025 ± 0.006 to 0.057 ± 0.004%·h−1 in rested, and 0.024 ± 0.007 to 0.072 ± 0.005%·h−1 in exercised muscle; P <0.0001) (treatment × time interaction effect; P <0.05). Postprandial FSRs trended to be greater in MYCO compared with MILK (0.065 ± 0.004 compared with 0.054 ± 0.004%·h−1, respectively; P = 0.093) and the postprandial rise in FSRs was greater in MYCO compared with MILK (Delta 0.040 ± 0.006 compared with Delta 0.018 ± 0.005%·h−1, respectively; P <0.01).
The ingestion of a single bolus of mycoprotein stimulates resting and postexercise muscle protein synthesis rates, and to a greater extent than a leucine-matched bolus of milk protein, in resistance-trained young men. This trial was registered at clinicaltrials.gov as 660065600.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Key points
We determined if bed rest increased mitochondrially derived reactive oxygen species and cellular redox stress, contributing to the induction of insulin resistance.
Bed rest decreased ...maximal and submaximal ADP‐stimulated mitochondrial respiration.
Bed rest did not alter mitochondrial H2O2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H2O2 emission to mitochondrial O2 consumption or markers of oxidative stress
The present data suggest strongly that mitochondrial H2O2 does not contribute to bed rest‐induced insulin resistance
Mitochondrial H2O2 has been causally linked to diet‐induced insulin resistance, although it remains unclear if muscle disuse similarly increases mitochondrial H2O2. Therefore, we investigated the potential that an increase in skeletal muscle mitochondrial H2O2 emission, potentially as a result of decreased ADP sensitivity, contributes to cellular redox stress and the induction of insulin resistance during short‐term bed rest in 20 healthy males. Bed rest led to a decline in glucose infusion rate during a hyperinsulinaemic‐euglycaemic clamp (−42 ± 2%; P < 0.001), and in permeabilized skeletal muscle fibres it decreased OXPHOS protein content (−16 ± 8%) and mitochondrial respiration across a range of ADP concentrations (−13 ± 5%). While bed rest tended to increase maximal mitochondrial H2O2 emission rates (P = 0.053), H2O2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H2O2 emission to mitochondrial O2 consumption, and markers of oxidative stress were not altered following bed rest. Altogether, while bed rest impairs mitochondrial ADP‐stimulated respiration, an increase in mitochondrial H2O2 emission does not contribute to the induction of insulin resistance following short‐term bed rest.
Key points
We determined if bed rest increased mitochondrially derived reactive oxygen species and cellular redox stress, contributing to the induction of insulin resistance.
Bed rest decreased maximal and submaximal ADP‐stimulated mitochondrial respiration.
Bed rest did not alter mitochondrial H2O2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H2O2 emission to mitochondrial O2 consumption or markers of oxidative stress
The present data suggest strongly that mitochondrial H2O2 does not contribute to bed rest‐induced insulin resistance
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Mycoprotein consumption has been shown to improve acute postprandial glycaemic control and decrease circulating cholesterol concentrations. We investigated the impact of incorporating mycoprotein ...into the diet on insulin sensitivity (IS), glycaemic control and plasma lipoprotein composition. Twenty healthy adults participated in a randomised, parallel-group trial in which they consumed a 7 d fully controlled diet where lunch and dinner contained either meat/fish (control group, CON) or mycoprotein (MYC) as the primary source of dietary protein. Oral glucose tolerance tests were performed pre- and post-intervention, and 24 h continuous blood glucose monitoring was applied throughout. Fasting plasma samples were obtained pre- and post-intervention and were analysed using quantitative, targeted NMR-based metabonomics. There were no changes within or between groups in blood glucose or serum insulin responses, nor in IS or 24 h glycaemic profiles. No differences between groups were found for 171 of the 224 metabonomic targets. Forty-five lipid concentrations of different lipoprotein fractions (VLDL, LDL, intermediate-density lipoprotein and HDL) remained unchanged in CON but showed a coordinated decrease (7–27 %; all P < 0·05) in MYC. Total plasma cholesterol, free cholesterol, LDL-cholesterol, HDL2-cholesterol, DHA and n-3 fatty acids decreased to a larger degree in MYC (14–19 %) compared with CON (3–11 %; P < 0·05). Substituting meat/fish for mycoprotein twice daily for 1 week did not modulate whole-body IS or glycaemic control but resulted in changes to plasma lipid composition, the latter primarily consisting of a coordinated reduction in circulating cholesterol-containing lipoproteins.
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