NT-proBNP for Predicting All-Cause Death and Heart Transplant in Children and Adults with Heart Failure.

Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) concentration is a heart failure (HF) biomarker in adults and children. Its prognostic value for HF-related events has been established only in adults. Therefore, we aimed to test the hypothesis that plasma NT-proBNP concentrations predicted the risk of heart transplantation or death in children with HF.

Algorithmic surveillance of ICU patients with acute respiratory distress syndrome (ASIC): protocol for a multicentre stepped-wedge cluster randomised quality improvement strategy.

Introduction: The acute respiratory distress syndrome (ARDS) is a highly relevant entity in critical care with mortality rates of 40%. Despite extensive scientific efforts, outcome-relevant therapeutic measures are still insufficiently practised at the bedside. Thus, there is a clear need to adhere to early diagnosis and sufficient therapy in ARDS, assuring lower mortality and multiple organ failure.

NT-proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT-proBNP/mortality relationship in real-world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT-proBNP / clinical event end-point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability.

The Developing Regorafenib Eye drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trial.

Aims: This programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age-related macular degeneration (nAMD).

Methods: Topical regorafenib was investigated in an open-label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 μl, 30 mg ml ) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best-corrected visual acuity (BCVA) from baseline to weeks 4 and 12.

Inhaled sGC Modulator Can Lower PH in Patients With COPD Without Deteriorating Oxygenation.

This study uses a highly fidelity computational simulator of pulmonary physiology to evaluate the impact of a soluble guanylate cyclase (sGC) modulator on gas exchange in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) as a complication. Three virtual patients with COPD were configured in the simulator based on clinical data. In agreement with previous clinical studies, modeling systemic application of an sGC modulator results in reduced partial pressure of oxygen (PaO ) and increased partial pressure of carbon dioxide (PaCO ) in arterial blood, if a drug-induced reduction of pulmonary vascular resistance (PVR) equal to that observed experimentally is assumed.

Estimation of Intra-vitreal Half-Lifes in the Rabbit Eye with Semi-mechanistic Equations.

Purpose: To develop an alternative method for estimating vitreal half-lifes in the rabbit eye based on simple equations for the physical processes of dissipation and the physiochemical properties of therapeutic substances applied by intravitreal drug administration.

Methods: Equations were derived to describe diffusion in the vitreous humor and permeation through the back-of-the-eye tissue, and the volume of distribution. The model was validated using reported half-life values from 83 compounds collected from literature.

Modeling and Simulation of In Vivo Drug Effects.

The concept of a pharmacokinetics-pharmacodynamics (PK/PD) assessment of drug development candidates is well established in pharmaceutical research and development, and PK/PD modeling is common practice in all pharmaceutical companies. A recent analysis (Morgan et al., Drug Discov Today 17(9-10):419-424, 2012) revealed however that insufficient certainty in the integrity of the causal chain of fundamental pharmacological steps from drug dosing through systemic exposure, target tissue exposure, and engagement of molecular target to pharmacological response is still the major driver of failure in phase II of clinical drug development.

How TK-TD and population models for aquatic macrophytes could support the risk assessment for plant protection products.

This case study of the Society of Environmental Toxicology and Chemistry (SETAC) workshop MODELINK demonstrates the potential use of mechanistic effects models for macrophytes to extrapolate from effects of a plant protection product observed in laboratory tests to effects resulting from dynamic exposure on macrophyte populations in edge-of-field water bodies. A standard European Union (EU) risk assessment for an example herbicide based on macrophyte laboratory tests indicated risks for several exposure scenarios. Three of these scenarios are further analyzed using effect models for 2 aquatic macrophytes, the free-floating standard test species Lemna sp.

A toxicokinetic and toxicodynamic modeling approach using Myriophyllum spicatum to predict effects caused by short-term exposure to a sulfonylurea.

Toxicokinetic and toxicodynamic models are a promising tool to address the effects of time-variable chemical exposure. Standard toxicity tests usually rely on static concentrations, but these chemical exposure patterns are unlikely to appear in the field, where time-variable exposure of chemicals is typical. In the present study, toxicodynamic processes were integrated into an existing model that includes the toxicokinetics and growth of the aquatic plant Myriophyllum spicatum, to predict the impact on plant growth of 2 iofensulfuron short-term exposure patterns.

An example of population-level risk assessments for small mammals using individual-based population models.

This article presents a case study demonstrating the application of 3 individual-based, spatially explicit population models (IBMs, also known as agent-based models) in ecological risk assessments to predict long-term effects of a pesticide to populations of small mammals. The 3 IBMs each used a hypothetical fungicide (FungicideX) in different scenarios: spraying in cereals (common vole, Microtus arvalis), spraying in orchards (field vole, Microtus agrestis), and cereal seed treatment (wood mouse, Apodemus sylvaticus). Each scenario used existing model landscapes, which differed greatly in size and structural complexity.

Toxicokinetic-toxicodynamic modeling of quantal and graded sublethal endpoints: a brief discussion of concepts.

We report on the advantages and problems of using toxicokinetic-toxicodynamic (TKTD) models for the analysis, understanding, and simulation of sublethal effects. Only a few toxicodynamic approaches for sublethal effects are available. These differ in their effect mechanism and emphasis on linkages between endpoints.

Improving uncertainty analysis in kinetic evaluations using iteratively reweighted least squares.

Kinetic parameters of environmental fate processes are usually inferred by fitting appropriate kinetic models to the data using standard nonlinear least squares (NLS) approaches. Although NLS is appropriate to estimate the optimum parameter values, it implies restrictive assumptions on data variances when the confidence limits of the parameters must also be determined. Particularly in the case of degradation and metabolite formation, the assumption of equal error variance is often not realistic because the parent data usually show higher variances than those of the metabolites.

Statistical analysis of chemical transformation kinetics using Markov-Chain Monte Carlo methods.

For the risk assessment of chemicals intentionally released into the environment, as, e.g., pesticides, it is indispensable to investigate their environmental fate.

Common errors and clinical guidelines for manual muscle testing: "the arm test" and other inaccurate procedures.

Background: The manual muscle test (MMT) has been offered as a chiropractic assessment tool that may help diagnose neuromusculoskeletal dysfunction. We contend that due to the number of manipulative practitioners using this test as part of the assessment of patients, clinical guidelines for the MMT are required to heighten the accuracy in the use of this tool.

Objective: To present essential operational definitions of the MMT for chiropractors and other clinicians that should improve the reliability of the MMT as a diagnostic test.

Whole body physiologically-based pharmacokinetic models: their use in clinical drug development.

Background: Whole-body physiologically-based pharmacokinetic (WB-PBPK) models mathematically describe an organism as a closed circulatory system consisting of compartments that represent the organs important for compound absorption, distribution, metabolism and elimination.

Objectives: To review the current state of WB-PBPK model use in the clinical phases of drug development.

Methods: A qualitative description of the WB-PBPK model structure is included along with a review of the varying methods available for input parameterisation.

Development of good modelling practice for physiologically based pharmacokinetic models for use in risk assessment: the first steps.

The increasing use of tissue dosimetry estimated using pharmacokinetic models in chemical risk assessments in various jurisdictions necessitates the development of internationally recognized good modelling practice (GMP). These practices would facilitate sharing of models and model evaluations and consistent applications in risk assessments. Clear descriptions of good practices for (1) model development i.

General approach for the calculation of tissue to plasma partition coefficients.

A new mechanistic, universal model for the calculation of steady state tissue:plasma partition coefficients (Kt:p) of organic chemicals in mammalian species was developed. The approach allows the estimation of Kt:p-values based on the composition of the tissues in terms of water, neutral lipids, neutral and acidic phospholipids and proteins using the lipophilicity, the binding to phospholipid membranes, the pKa and the unbound fraction in blood plasma as compound specific parameters. Taking explicitly into account the sign and fraction of the charge of the compounds at the physiological pH the method is universally applicable to neutral, acidic, basic or multiply charged substances and has thus a significantly extended applicability compared to previously published approaches.

Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs.

In clinical development stages, an a priori assessment of the sensitivity of the pharmacokinetic behavior with respect to physiological and anthropometric properties of human (sub-) populations is desirable. A physiology-based pharmacokinetic (PBPK) population model was developed that makes use of known distributions of physiological and anthropometric properties obtained from the literature for realistic populations. As input parameters, the simulation model requires race, gender, age, and two parameters out of body weight, height and body mass index.

Development and evaluation of a generic physiologically based pharmacokinetic model for children.

Background: Clinical trials in children are being encouraged by regulatory authorities in light of the immense off-label and unlicensed use of drugs in the paediatric population. The use of in silico techniques for pharmacokinetic prediction will aid in the development of paediatric clinical trials by guiding dosing regimens, ensuring efficient blood sampling times, maximising therapeutic effect and potentially reducing the number of children required for the study. The goal of this study was to extend an existing physiologically based pharmacokinetic (PBPK) model for adults to reflect the age-related physiological changes in children from birth to 18 years of age and, in conjunction with a previously developed age-specific clearance model, to evaluate the accuracy of the paediatric PBPK model to predict paediatric plasma profiles.

From physicochemistry to absorption and distribution: predictive mechanistic modelling and computational tools.

During the past decade, the pharmaceutical industry has invested considerably in technologies that have the potential to increase throughput in discovery projects. For large compound libraries, efficacy, availability and safety should be determined as early and as reliably as possible. The latest step in this effort is the implementation of in silico methods that combine and interpret (sometimes replace) experimental in vitro data.

A mechanistic approach for the scaling of clearance in children.

Background And Objective: Clearance is an important pharmacokinetic concept for scaling dosage, understanding the risks of drug-drug interactions and environmental risk assessment in children. Accurate clearance scaling to children requires prior knowledge of adult clearance mechanisms and the age-dependence of physiological and enzymatic development. The objective of this research was to develop and evaluate ontogeny models that would provide an assessment of the age-dependence of clearance.

Application of physiology-based pharmacokinetic and pharmacodynamic modeling to individualized target-controlled propofol infusions.

This study compared the ability of the physiology-based pharmacokinetic (PBPK) model with that of compartmental models used in propofol infusion devices to predict the pharmacokinetics and pharmacodynamics of propofol in various patient groups (children, pregnant women, young men, normal weight adults, and obese adults). With a PBPK model, loss of consciousness (LOC) and recovery of consciousness (ROC) corresponded to a narrow range of brain tissue concentrations (2.2-4.

Physiology-based pharmacokinetic modeling: ready to be used.

Physiology-based pharmacokinetic (PBPK) modeling is well recognized as a technology for mechanistically simulating and predicting the fate of substances in a mammalian body. Today, the demand for this methodology is higher than ever. The pharma industry and regulatory agencies are looking for new methods, which help to speed up and increase the efficiency of the development process for new drugs.

Physiology-based pharmacokinetic modeling: ready to be used.

Physiology-based pharmacokinetic (PBPK) modeling is well recognized as a technology for mechanistically simulating and predicting the fate of substances in a mammalian body. Today, the demand for this methodology is higher than ever. The pharma industry and regulatory agencies are looking for new methods, which help to speed up and increase the efficiency of the development process for new drugs.

A physiological model for the estimation of the fraction dose absorbed in humans.

A physiologically based model for gastrointestinal transit and absorption in humans is presented. The model can be used to study the dependency of the fraction dose absorbed (F(abs)) of both neutral and ionizable compounds on the two main physicochemical input parameters (the intestinal permeability coefficient (P(int)) and the solubility in the intestinal fluids (S(int))) as well as physiological parameters such as the gastric emptying time and the intestinal transit time. For permeability-limited compounds, the model produces the established sigmoidal dependence between F(abs) and P(int).