Reproductive toxicity in birds predicted by physiologically-based kinetics and bioenergetics modelling.

Effects on the growth and reproduction of birds are important endpoints in the environmental risk assessment (ERA) of pesticides. Toxicokinetic-toxicodynamic models based on dynamic energy budget theory (DEB) are promising tools to predict these effects mechanistically and make extrapolations relevant to ERA. However, before DEB-TKTD models are accepted as part of ERA for birds, ecotoxicological case studies are required so that stakeholders can assess their capabilities. We present such a case-study, modelling the effects of the fluopyram metabolite benzamide on the northern bobwhite quail (Colinus virginianus). We parametrised a DEB-TKTD model for the embryo stage on the basis of an egg injection study, designed to provide data for model development. We found that information on various endpoints, such as survival, growth, and yolk utilisation were needed to clearly distinguish between the performance of model variants with different TKTD assumptions. The calibration data were best explained when it was assumed that chemical uptake occurs via the yolk and that benzamide places stress on energy assimilation and mobilisation. To be able to bridge from the in vitro tests to real-life exposure, we developed a physiologically-based toxicokinetic (PBK) model for the quail and used it to predict benzamide exposure inside the eggs based on dietary exposure in a standard reproductive toxicity study. We then combined the standard DEB model with the TKTD module calibrated to the egg injection studies and used it to predict effects on hatchling and 14-day chick weight based on the exposure predicted by the PBK model. Observed weight reductions, relative to controls, were accurately predicted. Thus, we demonstrate that DEB-TKTD models, in combination with suitable experimental data and, if necessary, with an exposure model, can be used in bird ERA to predict chemical effects on reproduction.

A generic avian physiologically-based kinetic (PBK) model and its application in three bird species.

Physiologically-based kinetic (PBK) models are effective tools for designing toxicological studies and conducting extrapolations to inform hazard characterization in risk assessment by filling data gaps and defining safe levels of chemicals. In the present work, a generic avian PBK model for male and female birds was developed using PK-Sim and MoBi from the Open Systems Pharmacology Suite (OSPS). The PBK model includes an ovulation model (egg development) to predict concentrations of chemicals in eggs from dietary exposure. The model was parametrized for chicken (Gallus gallus), bobwhite quail (Colinus virginianus) and mallard duck (Anas platyrhynchos) and was tested with nine chemicals for which in vivo studies were available. Time-concentration profiles of chemicals reaching tissues and egg compartment were simulated and compared to in vivo data. The overall accuracy of the PBK model predictions across the analyzed chemicals was good. Model simulations were found to be in the range of 22-79% within a 3-fold and 41-89% were within 10- fold deviation of the in vivo observed data. However, for some compounds scarcity of in-vivo data and inconsistencies between published studies allowed only a limited goodness of fit evaluation. The generic avian PBK model was developed following a "best practice" workflow describing how to build a PBK model for novel species. The credibility and reproducibility of the avian PBK models were scored by evaluation according to the available guidance documents from WHO (2010), and OECD (2021), to increase applicability, confidence and acceptance of these in silico models in chemical risk assessment.

Quantitative Morphometric, Physiological, and Metabolic Characteristics of Chickens and Mallards for Physiologically Based Kinetic Model Development.

Physiologically based kinetic (PBK) models are a promising tool for xenobiotic environmental risk assessment that could reduce animal testing by predicting in vivo exposure. PBK models for birds could further our understanding of species-specific sensitivities to xenobiotics, but would require species-specific parameterization. To this end, we summarize multiple major morphometric and physiological characteristics in chickens, particularly laying hens (Gallus gallus) and mallards (Anas platyrhynchos) in a meta-analysis of published data. Where such data did not exist, data are substituted from domesticated ducks (Anas platyrhynchos) and, in their absence, from chickens. The distribution of water between intracellular, extracellular, and plasma is similar in laying hens and mallards. Similarly, the lengths of the components of the small intestine (duodenum, jejunum, and ileum) are similar in chickens and mallards. Moreover, not only are the gastrointestinal absorptive areas similar in mallard and chickens but also they are similar to those in mammals when expressed on a log basis and compared to log body weight. In contrast, the following are much lower in laying hens than mallards: cardiac output (CO), hematocrit (Hct), and blood hemoglobin. There are shifts in ovary weight (increased), oviduct weight (increased), and plasma/serum concentrations of vitellogenin and triglyceride between laying hens and sexually immature females. In contrast, reproductive state does not affect the relative weights of the liver, kidneys, spleen, and gizzard.

Quantitative Comparison of Avian and Mammalian Physiologies for Parameterization of Physiologically Based Kinetic Models.

Physiologically based kinetic (PBK) models facilitate chemical risk assessment by predicting in vivo exposure while reducing the need for animal testing. PBK models for mammals have seen significant progress, which has yet to be achieved for avian systems. Here, we quantitatively compare physiological, metabolic and anatomical characteristics between birds and mammals, with the aim of facilitating bird PBK model development. For some characteristics, there is considerable complementarity between avian and mammalian species with identical values for the following: blood hemoglobin and hemoglobin concentrations per unit erythrocyte volume together with relative weights of the liver, heart, and lungs. There are also systematic differences for some major characteristics between avian and mammalian species including erythrocyte volume, plasma concentrations of albumin, total protein and triglyceride together with liver cell size and relative weights of the kidney, spleen, and ovary. There are also major differences between characteristics between sexually mature and sexually immature female birds. For example, the relative weights of the ovary and oviduct are greater in sexually mature females compared to immature birds as are the plasma concentrations of triglyceride and vitellogenin. Both these sets of differences reflect the genetic "blue print" inherited from ancestral archosaurs such as the production of large eggs with yolk filled oocytes surrounded by egg white proteins, membranes and a calciferous shell together with adaptions for flight in birds or ancestrally in flightless birds.

Early prediction of decompensation (EPOD) score: Non-invasive determination of cirrhosis decompensation risk.

BACKGROUND & AIMS: Decompensation is a hallmark of disease progression in cirrhotic patients. Early detection of a phase transition from compensated cirrhosis to decompensation would enable targeted therapeutic interventions potentially extending life expectancy. This study aims to (a) identify the predictors of decompensation in a large, multicentric cohort of patients with compensated cirrhosis, (b) to build a reliable prognostic score for decompensation and (c) to evaluate the score in independent cohorts. METHODS: Decompensation was identified in electronic health records data from 6049 cirrhosis patients in the IBM Explorys database training cohort by diagnostic codes for variceal bleeding, encephalopathy, ascites, hepato-renal syndrome and/or jaundice. We identified predictors of clinical decompensation and developed a prognostic score using Cox regression analysis. The score was evaluated using the IBM Explorys database validation cohort (N = 17662), the Penn Medicine BioBank (N = 1326) and the UK Biobank (N = 317). RESULTS: The new Early Prediction of Decompensation (EPOD) score uses platelet count, albumin, and bilirubin concentration. It predicts decompensation during a 3-year follow-up in three validation cohorts with AUROCs of 0.69, 0.69 and 0.77, respectively, and outperforms the well-known MELD and Child-Pugh score in predicting decompensation. Furthermore, the EPOD score predicted the 3-year probability of decompensation. CONCLUSIONS: The EPOD score provides a prediction tool for the risk of decompensation in patients with cirrhosis that outperforms well-known cirrhosis scores. Since EPOD is based on three blood parameters, only, it provides maximal clinical feasibility at minimal costs.

A Model-Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs.

We present a generic workflow combining physiology-based computational modeling and in vitro data to assess the clinical cholestatic risk of different drugs systematically. Changes in expression levels of genes involved in the enterohepatic circulation of bile acids were obtained from an in vitro assay mimicking 14 days of repeated drug administration for 10 marketed drugs. These changes in gene expression over time were contextualized in a physiology-based bile acid model of glycochenodeoxycholic acid. The simulated drug-induced response in bile acid concentrations was then scaled with the applied drug doses to calculate the cholestatic potential for each compound. A ranking of the cholestatic potential correlated very well with the clinical cholestasis risk obtained from medical literature. The proposed workflow allows benchmarking the cholestatic risk of novel drug candidates. We expect the application of our workflow to significantly contribute to the stratification of the cholestatic potential of new drugs and to support animal-free testing in future drug development.

Network integration and modelling of dynamic drug responses at multi-omics levels.

Uncovering cellular responses from heterogeneous genomic data is crucial for molecular medicine in particular for drug safety. This can be realized by integrating the molecular activities in networks of interacting proteins. As proof-of-concept we challenge network modeling with time-resolved proteome, transcriptome and methylome measurements in iPSC-derived human 3D cardiac microtissues to elucidate adverse mechanisms of anthracycline cardiotoxicity measured with four different drugs (doxorubicin, epirubicin, idarubicin and daunorubicin). Dynamic molecular analysis at in vivo drug exposure levels reveal a network of 175 disease-associated proteins and identify common modules of anthracycline cardiotoxicity in vitro, related to mitochondrial and sarcomere function as well as remodeling of extracellular matrix. These in vitro-identified modules are transferable and are evaluated with biopsies of cardiomyopathy patients. This to our knowledge most comprehensive study on anthracycline cardiotoxicity demonstrates a reproducible workflow for molecular medicine and serves as a template for detecting adverse drug responses from complex omics data.

A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients.

Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.

Clinical significance of assertive community treatment among adolescents.

PURPOSE: The efficacy of assertive community treatment for children and adolescents is proven in the United States, but remains controversial in Europe. Moreover, most studies showing positive outcomes of assertive community treatment are limited to statistically significant differences and do not consider whether the treatment is also subjectively clinically meaningful for the patient. Using a naturalistic sample, the present study aims to assess statistical and clinical significance of an assertive community treatment unit for adolescents in Europe. METHODS: Linear mixed-effects models and reliable change indices were used to respectively assess the statistical and clinical significance of assertive community treatment in 179 adolescents (mean age = 15.76, SD = 1.76) with severe mental illnesses. RESULTS: Difficulties related to mental health (measured by the Health of the Nation Outcome Scales for Children and Adolescents, HoNOSCA) and overall functioning (measured by the Global Assessment of Functioning scale) statistically improved (all ps < 0.001) from admission to discharge. Additionally, a considerable proportion of patients (from 14% to 21%) clinically recovered to functional levels. CONCLUSION: Our results support the fact that assertive community treatment can have convincing and positive clinical outcomes in European settings.

Using quantitative systems pharmacology to evaluate the drug efficacy of COX-2 and 5-LOX inhibitors in therapeutic situations.

A quantitative analysis of dose-response relationships is essential in preclinical and clinical drug development in order to optimize drug efficacy and safety, respectively. However, there is a lack of quantitative understanding about the dynamics of pharmacological drug-target interactions in biological systems. In this study, a quantitative systems pharmacology (QSP) approach is applied to quantify the drug efficacy of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors by coupling physiologically based pharmacokinetic models, at the whole-body level, with affected biological networks, at the cellular scale. Both COX-2 and 5-LOX are key enzymes in the production of inflammatory mediators and are known targets in the design of anti-inflammatory drugs. Drug efficacy is here evaluated for single and appropriate co-treatment of diclofenac, celecoxib, zileuton, and licofelone by quantitatively studying the reduction of prostaglandins and leukotrienes. The impact of rifampicin pre-treatment on prostaglandin formation is also investigated by considering pharmacokinetic drug interactions with diclofenac and celecoxib, finally suggesting optimized dose levels to compensate for the reduced drug action. Furthermore, a strong correlation was found between pain relief observed in patients as well as celecoxib- and diclofenac-induced decrease in prostaglandins after 6 h. The findings presented reveal insights about drug-induced modulation of cellular networks in a whole-body context, thereby describing complex pharmacokinetic/pharmacodynamic behavior of COX-2 and 5-LOX inhibitors in therapeutic situations. The results demonstrate the clinical benefit of using QSP to predict drug efficacy and, hence, encourage its use in future drug discovery and development programs.

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation.

Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis, which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations.

Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application.

A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy.

Due to its high early bactericidal activity, isoniazid (INH) plays an essential role in tuberculosis treatment. Genetic polymorphisms of N-acetyltransferase type 2 (NAT2) cause a trimodal distribution of INH pharmacokinetics in slow, intermediate, and fast acetylators. The success of INH-based chemotherapy is associated with acetylator and patient health status. Still, a standard dose recommended by the FDA is administered regardless of acetylator type or immune status, even though adverse effects occur in 5 to 33% of all patients. Slow acetylators have a higher risk of development of drug-induced toxicity, while fast acetylators and immune-deficient patients face lower treatment success rates. To mechanistically assess the trade-off between toxicity and efficacy, we developed a physiologically based pharmacokinetic (PBPK) model describing the NAT2-dependent pharmacokinetics of INH and its metabolites. We combined the PBPK model with a pharmacodynamic (PD) model of antimycobacterial drug effects in the lungs. The resulting PBPK/PD model allowed the simultaneous simulation of treatment efficacies at the site of infection and exposure to toxic metabolites in off-target organs. Subsequently, we evaluated various INH dosing regimens in NAT2-specific immunocompetent and immune-deficient virtual populations. Our results suggest the need for acetylator-specific dose adjustments for optimal treatment outcomes. A reduced dose for slow acetylators substantially lowers the exposure to toxic metabolites and thereby the risk of adverse events, while it maintains sufficient treatment efficacies. Vice versa, intermediate and fast acetylators benefit from increased INH doses and a switch to a twice-daily administration schedule. Our analysis outlines how PBPK/PD modeling may be used to design and individualize treatment regimens.

Can the Health of the Nation Outcome Scales for Children and Adolescents predict the necessity of inpatient stay during assertive community treatment?

Understanding the trajectories of youths within Child and Adolescents Mental Health Service (CAMHS) is of primary importance. Our objective is to assess the usefulness of the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) to predict inpatient (IP) stay for youths followed by assertive community treatment (ACT) teams. 82 youths followed exclusively by ACT and 42 who needed IP were assessed with the HoNOSCA at admission to the program. The HoNOSCA allowed the computing of three scores: a total score, an externalizing symptoms (Ext) score and an emotional problems (Emo) score. Logistic regressions revealed that the three HoNOSCA scores at admission of ACT predicted later need for hospitalization. Using ROC curve analyses, we set up cut off scores with appropriate sensitivity and specificity for the HoNOSCA Total and Ext to optimally predict the need for hospitalization. This study revealed that the HoNOSCA may be a useful tool to predict the need for later IP during ACT. Such knowledge is important to set up the best therapeutic strategies.

Clinical Utility of the 2 New Scales of the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA): A Naturalistic, Prospective Study in a Psychiatric Unit for Adolescents.

OBJECTIVES: The goal of this study was to assess the clinical usefulness of the emotional symptoms (Emo) and externalizing problems (Ext) scales compared with the Total score on the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). METHODS: The HoNOSCA was rated at admission and discharge for 260 adolescent inpatients. The primary outcomes assessed were (a) the sensitivity of the 3 HoNOSCA scores to clinical improvement; and (b) the between diagnoses discriminative value of these scores. RESULTS: Analyses of variances [2 (time: admission vs. discharge) × 5 (diagnostic groups)] revealed a main effect of time for the 3 scores, a main effect of the diagnostic group for the Total and Ext scores, and an interaction effect between time and diagnosis for the Emo score. A moderate correlation was observed between the change in Ext and Emo scores between admission and discharge. DISCUSSION: These 2 new scales of the HoNOSCA demonstrated good clinical utility and the ability to assess different aspects of clinical improvements. A significant discriminative value of both scores was observed. SIGNIFICANT OUTCOMES: The clinical utility of the 2 new scales on the HoNOSCA was established. These 2 new scales provided a sensitive measure of clinical outcome for assessing improvement between admission and discharge on a psychiatric inpatient unit for adolescents, regardless of diagnostic group, and captured additional information about clinical improvements. Adolescents with psychosis and conduct disorders presented with higher externalizing symptoms than those with other disorders, as rated on the HoNOSCA, at admission and discharge. The Emo score differentiated between clinical improvement in patients with psychosis versus eating disorders. LIMITATIONS: The sample in this study represented a homogeneous population of adolescent inpatients, so that further research is needed before these findings can be generalized to outpatients. In addition, the small number of patients in some diagnostic groups did not allow for their inclusion in some of the statistical analyses.

Predictors and Moderators of Clinical Outcomes in Adolescents with Severe Mental Disorders After an Assertive Community Treatment.

Previous studies have shown that stressful life events (SLEs), gender, social functioning and pretreatment severity are some of the predictors and/or moderators of treatment outcome in psychiatric care. The current study explored the effect of these predictors and moderators on the treatment outcome related to assertive community treatment (ACT) proposed to young people with severe mental disorders. 98 patients were assessed for externalizing and emotional difficulties, at admission and then at discharge of an ACT. Analyses revealed significant improvements in terms of symptomatology. In particular, regression analyses showed that pretreatment severity is a significant predictor of the outcome on emotional symptoms and is moderated by SLE on the outcome on externalizing symptoms. Furthermore, higher social functioning proved to predict better outcome on externalizing symptoms. Our results further evidence that these factors can explain inter-individual differences in outcome related to ACT. The theoretical and clinical implications of these results are discussed.

The French adaptation of the Health of the Nation Outcome Scale for Children and Adolescents Self-Rated Form (F-HoNOSCA-SR): validation and clinical routine use.

The current study aimed to explore the validity of an adaptation into French of the self-rated form of the Health of the Nation Outcome Scales for Children and Adolescents (F-HoNOSCA-SR) and to test its usefulness in a clinical routine use. One hundred and twenty nine patients, admitted into two inpatient units, were asked to participate in the study. One hundred and seven patients filled out the F-HoNOSCA-SR (for a subsample (N=17): at two occasions, one week apart) and the strengths and difficulties questionnaire (SDQ). In addition, the clinician rated the clinician-rated form of the HoNOSCA (HoNOSCA-CR, N=82). The reliability (assessed with split-half coefficient, item response theory (IRT) models and intraclass correlations (ICC) between the two occasions) revealed that the F-HoNSOCA-SR provides reliable measures. The concurrent validity assessed by correlating the F-HoNOSCA-SR and the SDQ revealed a good convergent validity of the instrument. The relationship analyses between the F-HoNOSCA-SR and the HoNOSCA-CR revealed weak but significant correlations. The comparison between the F-HoNOSCA-SR and the HoNOSCA-CR with paired sample t-tests revealed a higher score for the self-rated version. The F-HoNSOCA-SR was reported to provide reliable measures. In addition, it allows us to measure complementary information when used together with the HoNOSCA-CR.

Early tailored assertive community case management for hard-to-engage adolescents suffering from psychiatric disorders: an exploratory pilot study.

AIM: The study aims to evaluate the effects of assertive community treatment (ACT) on the mental health and overall functioning of adolescents suffering from severe psychiatric disorders and who refuse any traditional child psychiatric care. There are a few studies evaluating the effects of ACT on a population of adolescents with psychiatric disorders. This short report highlights the impact of an ACT programme tailored to the needs of these patients, not only as an alternative to hospitalization, but also as a new form of intervention for patients that are difficult to engage. METHODS: The effect of ACT on 35 adolescents using the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) as a measuring tool in pre- and post-intervention was evaluated. RESULTS: The results show that the intervention was associated with a significant improvement on the HoNOSCA overall score, with the following items showing significant amelioration: hyperactivity/focus problems, non-organic somatic symptoms, emotional symptoms, scholastic/language skills, peer relationships, family relationships and school attendance. CONCLUSION: ACT appears as a feasible intervention for hard-to-engage adolescents suffering from psychiatric disorders. The intervention seems to improve their mental health and functioning. This pilot study may serve as a basis to prepare a controlled study that will also take the costs of the intervention into account.