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A growing number of population pharmacokinetic analyses of therapeutic monoclonal antibodies (mAbs) have been published in the scientific literature. The aims of this article are to summarize the findings from these studies and to relate the findings to the general pharmacokinetic and structural characteristics of therapeutic mAbs. A two-compartment model was used in the majority of the population analyses to describe the disposition of the mAb. Population estimates of the volumes of distribution in the central (V 1 ) and peripheral (V 2 ) compartments were typically small, with median (range) values of 3.1 (2.4–5.5) L and 2.8 (1.3–6.8) L, respectively. The estimated between-subject variability in the V 1 was usually moderate, with a median (range) coefficient of variation (CV) of 26% (12–84%). Between-subject variability in other distribution-related parameters such as the V 2 and intercompartmental clearance were often not estimated. Although the pharmacokinetic models used most frequently in the population analyses were models with linear clearance, other models with nonlinear, or parallel linear and nonlinear clearance pathways were also applied, as many therapeutic mAbs are eliminated via saturable target-mediated mechanisms. Population estimates of the maximum elimination rate (V max ) and the mAb concentration at which elimination was at half maximum for Michaelis-Menten-type elimination pathways varied considerably among the different therapeutic mAbs. However, estimates of the total clearance (CL) of mAbs with linear clearance characteristics and of the clearance of mAbs via the linear clearance pathway (CL L ) with parallel linear and nonlinear clearance were quite similar for the different mAbs and typically ranged from 0.2 to 0.5 L/day, which is relatively close to the estimated clearance of endogenous IgG of 0.21 L/day. The between-subject variability in the V max , CL and CL L was moderate to high, with estimated CVs ranging from 15% to 65%. Measures of body size were the covariates most commonly identified as influencing the pharmacokinetics of therapeutic mAbs. In summary, many features of the population pharmacokinetics of currently used therapeutic mAbs are similar, despite differences in their pharmacological targets and studied patient populations.

Alzheimer’s disease (AD) is the most common neurodegenerative disease. Pathological proteins of AD mainly contain amyloid-beta (Aβ) and tau. Their deposition will lead to neuron damage by a series of pathways, and then induce memory and cognitive impairment. Thus, it is pivotal to understand the clearance pathways of Aβ and tau in order to delay or even halt AD. Aβ clearance mechanisms include ubiquitin–proteasome system, autophagy-lysosome, proteases, microglial phagocytosis, and transport from the brain to the blood via the blood-brain barrier (BBB), arachnoid villi and blood-CSF barrier, which can be named blood circulatory clearance. Recently, lymphatic clearance has been demonstrated to play a key role in transport of Aβ into cervical lymph nodes. The discovery of meningeal lymphatic vessels is another direct evidence for lymphatic clearance in the brain. Furthermore, periphery clearance also contributes to Aβ clearance. Tau clearance is almost the same as Aβ clearance. In this review, we will mainly introduce the clearance mechanisms of Aβ and tau proteins, and summarize corresponding targeted drug therapies for AD.

Early prediction of clearance mechanisms allows for the rapid progression of drug discovery and development programs, and facilitates risk assessment of the pharmacokinetic variability associated with drug interactions and pharmacogenomics. Here we propose a scientific framework – Extended Clearance Classification System (ECCS) – which can be used to predict the predominant clearance mechanism (rate-determining process) based on physicochemical properties and passive membrane permeability. Compounds are classified as: Class 1A – metabolism as primary systemic clearance mechanism (high permeability acids/zwitterions with molecular weight (MW) ≤400 Da), Class 1B – transporter-mediated hepatic uptake as primary systemic clearance mechanism (high permeability acids/zwitterions with MW >400 Da), Class 2 – metabolism as primary clearance mechanism (high permeability bases/neutrals), Class 3A –renal clearance (low permeability acids/zwitterions with MW ≤400 Da), Class 3B – transporter mediated hepatic uptake or renal clearance (low permeability acids/zwitterions with MW >400 Da), and Class 4 – renal clearance (low permeability bases/neutrals). The performance of the ECCS framework was validated using 307 compounds with single clearance mechanism contributing to ≥70% of systemic clearance. The apparent permeability across clonal cell line of Madin − Darby canine kidney cells, selected for low endogenous efflux transporter expression, with a cut-off of 5 × 10 −6  cm/s was used for permeability classification, and the ionization (at pH7) was assigned based on calculated pKa. The proposed scheme correctly predicted the rate-determining clearance mechanism to be either metabolism, hepatic uptake or renal for ~92% of total compounds. We discuss the general characteristics of each ECCS class, as well as compare and contrast the framework with the biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS). Collectively, the ECCS framework is valuable in early prediction of clearance mechanism and can aid in choosing the right preclinical tool kit and strategy for optimizing drug exposure and evaluating clinical risk of pharmacokinetic variability caused by drug interactions and pharmacogenomics.

Alterations of cell death pathways, including apoptosis and the neutrophil specific kind of death called NETosis, can represent a potential source of autoantigens. Defects in the clearance of apoptotic cells may be responsible for the initiation of systemic autoimmunity in several chronic inflammatory diseases, including systemic lupus erythematosus (SLE). Autoantigens are released mainly from secondary necrotic cells because of a defective clearance of apoptotic cells or an inefficient degradation of DNA-containing neutrophil extracellular traps (NETs). These modified autoantigens are presented by follicular dendritic cells to autoreactive B cells in germinal centers of secondary lymphoid organs. This results in the loss of self-tolerance and production of autoantibodies, a unifying feature of SLE. Immune complexes (IC) are formed from autoantibodies bound to uncleared cellular debris in blood or tissues. Clearance of IC by blood phagocytes, macrophages, and dendritic cells leads to proinflammatory cytokine secretion. In particular, plasmacytoid dendritic cells produce high amounts of interferon-α upon IC uptake, thereby contributing to the interferon signature of patients with SLE. The clearance of antinuclear IC via Fc-gamma receptors is considered a central event in amplifying inflammatory immune responses in SLE. Along with this, the accumulation of cell remnants represents an initiating event of the etiology, while the subsequent generation of autoantibodies against nuclear antigens (including NETs) results in the perpetuation of inflammation and tissue damage in patients with SLE. Here, we discuss the implications of defective clearance of apoptotic cells and NETs in the development of clinical manifestations in SLE.

Due to its structural characteristics, the Kaplan turbine has a specific tip clearance between blade and chamber of the runner. This paper simulates effect of varied runner tip clearance on hydraulic performance of Kaplan turbine by CFD, and model tests validated the results. The results show that the efficiency and cavitation level of turbine will decrease with the increase of runner tip clearance within a specific range.

Background and Objective Sepsis and continuous renal replacement therapy (CRRT) can both significantly affect antifungal pharmacokinetics. This study aimed to describe the pharmacokinetics of caspofungin in critically ill patients during different CRRT modes. Methods Patients receiving caspofungin and undergoing continuous veno-venous haemofiltration (CVVH) or haemodiafiltration (CVVHDF) were eligible to take part in the study. Blood samples were collected at seven sampling times during a dosing interval. Demographics and clinical data were recorded. Population pharmacokinetic analysis and Monte-Carlo simulation were undertaken using Pmetrics. Results Twelve pharmacokinetic profiles from nine patients were analysed. The caspofungin CRRT clearance (CL) was 0.048 ± 0.12 L/h for CVVH and 0.042 ± 0.042 L/h for CVVHDF. A two-compartment linear model best described the data. Patient weight was the only covariate affecting drug CL and central volume. The mean (standard deviation) parameter estimates were 0.64 ± 0.12 L/h for CL, 9.35 ± 3.56 L for central volume, 0.25 ± 0.19 per h for the rate constant for drug distribution from central to peripheral compartments and 0.19 ± 0.10 per h from peripheral to central compartments. Based on simulation results, a caspofungin 100 mg loading dose followed by a 50 mg maintenance dose for patients with a total body weight of ≤80 kg best achieved the pharmacokinetic/PD targets whilst a 70 mg maintenance dose was required for patients with a weight of >80 kg. Conclusion No caspofungin dosing adjustment is necessary for patients undergoing either form of CRRT. However, higher than recommended loading doses of caspofungin are required to achieve pharmacokinetic/pharmacodynamic targets in critically ill patients. Registration: ClinicalTrials.gov Identifier NCT01403220

Streptococcus intermedius occasionally causes brain abscesses that can be life-threatening, requiring prompt antibiotic and neurosurgical treatment. The source is often dental, and it may spread to the eye or the brain parenchyma. We report the case of a 34-year-old man with signs of apical periodontitis, endophthalmitis, and multiple brain abscesses caused by Streptococcus intermedius . Initial treatment with meropenem and vancomycin was unsuccessful due to subtherapeutic concentrations, despite recommended dosages. Adequate concentrations could be reached only after increasing the dose of meropenem to 16 g/day and vancomycin to 1.5 g × 4. The patient exhibited high creatinine clearance consistent with augmented renal clearance, although iohexol and cystatin C clearances were normal. Plasma free vancomycin clearance followed that of creatinine. A one-day dose of trimethoprim–sulfamethoxazole led to an increase in serum creatinine and a decrease in both creatinine and urea clearances. These results indicate that increased tubular secretion of the drugs was the cause of suboptimal antibiotic treatment. The patient eventually recovered, but his left eye needed enucleation. Our case illustrates that augmented renal clearance can jeopardize the treatment of serious bacterial infections and that high doses of antibiotics are needed to achieve therapeutic concentrations in such cases. The mechanisms for regulation of kidney tubular transporters of creatinine, urea, vancomycin, and meropenem in critically ill patients are discussed.

The revolute pair and translational pair are the two most important kinematic pairs in planar mechanism. Their clearances directly affect the accuracy of planar mechanism. In addition, flexible components will also lead to a certain degree of vibration and shaking of the mechanism, which will seriously affect the stability. In this paper, considering the coupling effect of revolute clearance pair, translational clearance pair and elastic deformation of components, an accurate dynamic modeling method of rigid-flexible coupling multi-link mechanism (MLM) considering revolute clearance and translational clearance is proposed to accurately predict the nonlinear behavior. Clearance models of revolute pair and translational pair are established, the flexible element model is established based on the absolute node coordinate formulation (ANCF), and the nonlinear dynamic equation of rigid-flexible coupling six-bar mechanism considering the clearance of revolute pair and translational pair is built by Lagrange multiplier method (LMD). Dynamic response and chaos identification are researched. Chaos identification is determined qualitatively and quantitatively by phase diagram, Poincaré map and largest Lyapunov exponent. Influences of different clearance values and driving speeds on nonlinear dynamic behavior of mechanism are discussed. Bifurcation diagrams varying with clearance size and driving velocity are studied, respectively. Dynamic modeling method is compared and verified by ADAMS. The experimental platform of six-bar mechanism is built to further verify the correctness of theoretical model.

Background Myoglobin clearance in acute kidney injury requiring renal replacement therapy is important because myoglobin has direct renal toxic effects. Clinical data comparing different modalities of renal replacement therapy addressing myoglobin clearance are limited. This study aimed to compare two renal replacement modalities regarding myoglobin clearance. Methods In this prospective, randomized, single-blinded, single-center trial, 70 critically ill patients requiring renal replacement therapy were randomized 1:1 into an intervention arm using continuous veno-venous hemodialysis with high cutoff dialyzer and a control arm using continuous veno-venous hemodiafiltration postdilution with high-flux dialyzer. Regional citrate anticoagulation was used in both groups to maintain the extracorporeal circuit. The concentrations of myoglobin, urea, creatinine, β2-microglobulin, interleukin-6 and albumin were measured before and after the dialyzer at 1 h, 6 h, 12 h, 24 h and 48 h after initiating continuous renal replacement therapy. Results Thirty-three patients were allocated to the control arm (CVVHDF with high-flux dialyzer) and 35 patients to the intervention arm (CVVHD with high cutoff dialyzer). Myoglobin clearance, as a primary endpoint, was significantly better in the intervention arm than in the control arm throughout the whole study period. The clearance values for urea and creatinine were higher in the control arm. There was no measurable albumin clearance in both arms. The clearance data for β 2 -microglobulin and interleukin-6 were non-inferior in the intervention arm compared to those for the control arm. Dialyzer lifespan was 57.0 [38.0, 72.0] hours in the control arm and 70.0 [56.75, 72.0] hours in the intervention arm ( p  = 0.029). Conclusions Myoglobin clearance using continuous veno-venous hemodialysis with high cutoff dialyzer and regional citrate anticoagulation is better than that with continuous veno-venous hemodiafiltration with regional citrate anticoagulation. Trial registration German Clinical Trials Registry (DRKS00012407); date of registration 23/05/2017. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012407 .

Pathogens and inflammatory conditions rapidly induce the expression of immune-responsive gene 1 (IRG1) in cells of myeloid lineage. IRG1 encodes an aconitate decarboxylase (ACOD1) that produces the immunomodulatory metabolite itaconate (ITA). In addition to rapid intracellular accumulation, ITA is also secreted from the cell, but whether secreted ITA functions as a signaling molecule is unclear. Here, we identified ITA as an orthosteric agonist of the GPCR OXGR1, with an EC50 of approximately 0.3 mM, which was in the same range as the physiological concentration of extracellular ITA upon macrophage activation. ITA activated OXGR1 to induce Ca2+ mobilization, ERK phosphorylation, and endocytosis of the receptor. In a mouse model of pulmonary infection with bacterial Pseudomonas aeruginosa, ITA stimulated Oxgr1-dependent mucus secretion and transport in respiratory epithelium, the primary innate defense mechanism of the airway. Our study thus identifies ITA as a bona fide ligand for OXGR1 and the ITA/OXGR1 paracrine signaling pathway during the pulmonary innate immune response.