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Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-33-2015 | Award Amount: 30.12M | Year: 2016

The vision of EU-ToxRisk is to drive a paradigm shift in toxicology towards an animal-free, mechanism-based integrated approach to chemical safety assessment. The project will unite all relevant disciplines and stakeholders to establish: i) pragmatic, solid read-across procedures incorporating mechanistic and toxicokinetic knowledge; and ii) ab initio hazard and risk assessment strategies of chemicals with little background information. The project will focus on repeated dose systemic toxicity (liver, kidney, lung and nervous system) as well as developmental/reproduction toxicity. Different human tiered test systems are integrated to balance speed, cost and biological complexity. EU-ToxRisk extensively integrates the adverse outcome pathway (AOP)-based toxicity testing concept. Therefore, advanced technologies, including high throughput transcriptomics, RNA interference, and high throughput microscopy, will provide quantitative and mechanistic underpinning of AOPs and key events (KE). The project combines in silico tools and in vitro assays by computational modelling approaches to provide quantitative data on the activation of KE of AOP. This information, together with detailed toxicokinetics data, and in vitro-in vivo extrapolation algorithms forms the basis for improved hazard and risk assessment. The EU-ToxRisk work plan is structured along a broad spectrum of case studies, driven by the cosmetics, (agro)-chemical, pharma industry together with regulators. The approach involves iterative training, testing, optimization and validation phases to establish fit-for-purpose integrated approaches to testing and assessment with key EU-ToxRisk methodologies. The test systems will be combined to a flexible service package for exploitation and continued impact across industry sectors and regulatory application. The proof-of-concept for the new mechanism-based testing strategy will make EU-ToxRisk the flagship in Europe for animal-free chemical safety assessment.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-1.3-1 | Award Amount: 16.43M | Year: 2008

The overall aim of Predict-IV is to develop strategies to improve the assessment of drug safety in the early stage of development and late discovery phase, by an intelligent combination of non animal-based test systems, cell biology, mechanistic toxicology and in-silico modelling, in a rapid and cost effective manner. A better prediction of the safety of an investigational compound in early development will be delivered. Margins-of-safety will be deduced and the data generated by the proposed approach may also identify early biomarkers of human toxicity for pharmaceuticals. The results obtained in Predict-IV will enable pharmaceutical companies to create a tailored testing strategy for early drug safety. The project will integrate new developments to improve and optimize cell culture models for toxicity testing and to characterize the dynamics and kinetics of cellular responses to toxic effects in vitro. The target organs most frequently affected by drug toxicity will be taken into account, namely liver and kidney. Moreover, predictive models for neurotoxicty are scarce and will be developed. For each target organ the most appropriate cell model will be used. The approach will be evaluated using a panel of drugs with well described toxicities and kinetics in animals and partly also in humans. This approach will be highly advantageous as it will allow a direct comparison between the in vivo to the in vitro data. A parallel analysis of several dynamic and kinetic models with a broad spectrum of endpoints should allow for the identification of several relevant biomarkers of toxicity. Inter-individual susceptibilities will be taken into account by integrating the polymorphisms of the major drug metabolizing enzymes and correlating the observed effects in the human cell models with their genotype. Environmental influences on cellular toxicity to these compounds will also be evaluated using hypoxic stress as a relevant test model.


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2016 | Award Amount: 3.93M | Year: 2016

Ocular drug development has transformed from niche area to a major field in drug development in which many companies, including European big pharma has entered recently. Ocular drug development is a unique field in terms of drug targets and end-points of activity, local drug administration routes, tissue barriers and pharmacokinetics, drug delivery and formulation challenges and local toxicity issues. These issues are slowing down the development of drugs for the unmet needs in ophthalmology. The main objective of the proposal is to educate experts of preclinical ocular R&D to facilitate the success of European pharmaceutical industry and research community. This objective will be reached by joining forces of the leading European academic and industrial researchers in ophthalmology, materials science and nanomedicine, drug delivery and targeting, and systems pharmacology. We shall educate 15 Early Stage Researchers in a network where they will receive tailored, multi-disciplinary and inter-sectoral education in preclinical ocular drug development. The thesis projects are directed to the drug treatment of retinal diseases, the major challenge in the field. The proposal combines new drug candidates from the experts of ophthalmology, innovative drug delivery technologies from pharmaceutical scientists and companies, and modern in vitro, in silico and in vivo methods from various partners. The thesis projects include secondments in academic and industrial partner laboratories and course programme that encompasses the relevant fields in ocular drug development. Therefore, this proposal presents unique combination of innovation and education in the field with obvious need for such education. The ESRs and other outcomes of this project will greatly benefit the future competitiveness of European science and industry in this field of expanding importance.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2011.4.2-1 | Award Amount: 5.52M | Year: 2011

The aim of TAIN is to develop a neonatal formulation of hydrocortisone, a drug included in the EMA priority list that needs specific evaluation in the age range 0 2 years (neonates & infants). Hydrocortisone is an essential glucocorticoid hormone used as replacement therapy for the treatment of congenital and acquired adrenal insufficiency as well playing an important therapeutic role in oncology in infants, specifically brain tumours and leukaemias. TAIN involves European leaders in neonatology, paediatric pharmacology, methodology and SMEs that will establish links with ethical bodies and regulatory authorities. The programme will perform in silico experiments and evaluate formulations for neonates. The phase 3 clinical trial comparing the neonatal hydrocortisone versus current (unlicensed) therapy will be optimized using age-appropriate state-of-the-art methods adapted to neonates (including in silico experiments and pharmacokinetics) to validate the components of a Paediatric Investigation Plan. It will be performed by neonatologists trained in paediatric pharmacology and clinical research in line with guidelines on Good Clinical Practice. All the ethical issues will be considered, including pain and distress, blood sampling (number and volume) and informed consent. Parent information sheets and consent form will be submitted to patient and parents associations for approval. TAIN will include short term safety studies and Phase 3 clinical studies in neonates and infants. Results will be reported in order to allow a PUMA application to be submitted and to improve neonatal and infant care. Therefore, TAIN will validate the appropriate use of hydrocortisone in neonates and infants which will be of direct benefit to children, their families and health professionals. TAIN will strengthen paediatric drug evaluation across Europe and build up a network of units with experience in clinical research that will be used for additional drug evaluation in neonates.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.2.1-4 | Award Amount: 4.19M | Year: 2010

Brain diseases are one of the most prevalent groups of diseases in Europe with estimated annual costs amounting to 386 billion (1). Data collected by the WHO suggest that brain diseases are responsible for 35% of Europes total disease burden (1). In the treatment of neurological disease, the blood brain barrier (BBB) still represents an obstacle for the delivery of drugs to the brain and thus a major challenge for the development of therapeutic regimens. Understanding the molecular basis and functioning of the BBB in health and disease, including transport mechanisms across the BBB, therefore holds significant potential for future strategies to prevent and ameliorate neurological disease. Recent research indicates that some neurological disorders have a developmental etiologic component. The major goal of the NEUROBID project is thus to understand the molecular mechanisms and function of the BBB in health and disease both in the developing brain and the adult central nervous system. With an interdisciplinary consortium from the fields of developmental neurobiology and BBB research, NEUROBID aims to (i) understand the involvement of normal and disturbed BBB function in normal and abnormal brain development and (ii) to develop novel strategies for drug delivery to the brain. Unique transport mechanisms across the BBB will be used to target potential therapeutic macromolecular and cellular agents specifically to the brain barriers and transport them into the brain. The main target disorders of NEUROBID are non-inherited neurodevelopmental disorders arising from perinatal adverse exposure, such as cerebral palsy, and classic adult neurological disorders such as multiple sclerosis and stroke. In the long term, NEUROBID hopes to pave the way for new treatment strategies and thus reduce the economic and social burden of neurological disease. 1. Olesen J, et al. Consensus document on European brain research. J Neurol Neurosurg Psychiatry 2006;77 Suppl 1:i1-49.


Tsamandouras N.,University of Manchester | Rostami-Hodjegan A.,University of Manchester | Rostami-Hodjegan A.,Simcyp Ltd | Aarons L.,University of Manchester
British Journal of Clinical Pharmacology | Year: 2015

Pharmacokinetic models range from being entirely exploratory and empirical, to semi-mechanistic and ultimately complex physiologically based pharmacokinetic (PBPK) models. This choice is conditional on the modelling purpose as well as the amount and quality of the available data. The main advantage of PBPK models is that they can be used to extrapolate outside the studied population and experimental conditions. The trade-off for this advantage is a complex system of differential equations with a considerable number of model parameters. When these parameters cannot be informed from in vitro or in silico experiments they are usually optimized with respect to observed clinical data. Parameter estimation in complex models is a challenging task associated with many methodological issues which are discussed here with specific recommendations. Concepts such as structural and practical identifiability are described with regards to PBPK modelling and the value of experimental design and sensitivity analyses is sketched out. Parameter estimation approaches are discussed, while we also highlight the importance of not neglecting the covariance structure between model parameters and the uncertainty and population variability that is associated with them. Finally the possibility of using model order reduction techniques and minimal semi-mechanistic models that retain the physiological-mechanistic nature only in the parts of the model which are relevant to the desired modelling purpose is emphasized. Careful attention to all the above issues allows us to integrate successfully information from in vitro or in silico experiments together with information deriving from observed clinical data and develop mechanistically sound models with clinical relevance. © 2013 The British Pharmacological Society.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.4.2-1 | Award Amount: 6.54M | Year: 2011

The aim of TINN2 is to evaluate azithromycin, included in the EMEA priority list of the therapeutic areas that need specific drug evaluation in preterm and term neonates. Azithromycin is a macrolid antibiotic with anti-inflammatory properties active against Ureaplasma. It might be effective in reducing the severity of bronhopulmonary disease in which Ureaplasma infection and inflammation play a role. TINN2 involves European leaders in neonatology, paediatric pharmacology, methodology and SMEs that will establish links with ethical bodies and regulatory authorities. The programme will perform in silico experiments and evaluate formulations for neonates. The randomized placebo-controlled trial will be optimized using age-appropriate state-of-the-art methods adapted to neonates (including in silico experiments, pharmacokinetics and pharmacogenetics) to validate the components of a Paediatric Investigation Plan. It will be performed by neonatologists trained in paediatric pharmacology and clinical research in line with guidelines on Good Clinical Practice. All the ethical issues will be considered, including pain and distress, blood sampling (number and volume) and informed consent. Parent information sheets and consent form will be submitted to parents associations for approval. TINN2 will include short term safety and potential for long term adverse reactions. Results will be reported in order to allow a PUMA application and to improve neonatal care. Therefore, TINN2 will validate the appropriate use of azithromycin in neonates which will be of direct benefit to children, their families and health professionals. TINN2 will strengthen paediatric drug evaluation across Europe, support recent initiatives from the European pharmaceutical industry and build up a network of units with experience in clinical research that will be used for additional drug evaluation in neonates.


Jones H.M.,Pfizer | Rowland-Yeo K.,Simcyp Ltd.
CPT: Pharmacometrics and Systems Pharmacology | Year: 2013

The aim of this tutorial is to introduce the concept of physiologically based pharmacokinetic (PBPK) modeling to individuals in the pharmaceutical industry who may be relatively new to this area and to demonstrate application of this approach in a preclinical and clinical setting. The tutorial provides some background on PBPK models and their data requirements, introduces strategies for PBPK modeling in drug development, and includes a discussion on regulatory considerations and potential resource issues. © 2013 ASCPT All rights reserved.


Plowchalk D.R.,Pfizer | Rowland Yeo K.,Simcyp Ltd
European Journal of Clinical Pharmacology | Year: 2012

Purpose To derive estimates of CYP1A2 abundance as a function of daily cigarette consumption and use these values to predict the clearances of CYP1A2 substrates in smokers. Methods Smoking-induced changes in hepatic CYP1A2 abundance were extrapolated from reported in vivo caffeine clearance data for sub-groups of a smoking population that were categorized according to their daily cigarette consumption. These abundance values together with in vitro-in vivo extrapolation (IVIVE) within the Simcyp population-based Simulator were used to predict the clearances of caffeine, theophylline, and clozapine in smokers. The model was used subsequently to predict differences in oral clearance between smoker and non-smoker cohorts in a Phase 1 clinical trial involving PF-2400013, a drug metabolized by CYP1A2. Results Estimated hepatic CYP1A2 abundance values were 52, 64, 79, 90, and 94 pmol/mg microsomal protein for subjects smoking 0, 1-5, 6-10, 11-20, and >20 cigarettes/day respectively. Predicted-fold increases in oral clearance of caffeine, theophylline and clozapine in smokers relative to non-smokers were consistent with observed data. The validated model was able to recover the smoking-induced increase in oral clearance of PF-2400013; predicted and observed mean (CV%) values in male nonsmokers and smokers were 90 L/h (40%) and 141 L/h (34%) respectively, and 100 L/h (58%) and 131 L/h (33%) respectively. Conclusions This study demonstrates that it may be possible to predict the clearance of CYP1A2 substrates in smoking populations using quantitative estimates of CYP1A2 abundance based on daily cigarette consumption in conjunction with an IVIVE approach. © Springer-Verlag 2012.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Smart - Development of Prototype | Award Amount: 87.79K | Year: 2012

In vitro-in vivo extrapolation (IVIVE) is a rapidly emerging area in drug development whereby in vitro experimental pharmacokinetic / pharmacodynamic (PK-PD) data, generated in tissue homogenates or cells, are analysed and the results incorporated into computer models to predict the effects of drugs in the whole body. PK-PD data analysis in whole cell systems is complex and time consuming, yet accurate data analysis and informed data interpretation are crucial in early drug development as this information is used to select drugs to be assessed in human trials. Whilst there are many software tools available for in vitro data analysis, these tools were developed for broad application and are not specialised for drug development use. The tools do not support analysis of more complex in vitro experimental systems which are increasingly being used in an attempt to overcome newer challenges in drug development, lack appropriate statistical rigour and do not allow IVIVE. The project will provide a user-friendly software tool to analyse in vitro data describing the metabolism, transport and receptor binding of drugs in the first instance. The experimental uncertainty arising from the data analysis will also be determined. The results derived from the in vitro data analysis and any associated uncertainty will be extrapolated to describe the behaviour of the drug within the whole body. The tool will enable non-expert users to determine the quality of the generated in vitro data, and the appropriateness of using the estimated parameters in the decision making process. The development and utilisation of this tool will allow consistency in data analysis across the pharmaceutical industry. Use of the tool will ultimately lead to improved efficiency and increase the utility of IVIVE and pharmacokinetic / pharmacodynamic understanding in drug development. In turn, increased use of IVIVE will contribute to reducing and replacing animal experiments within early drug development.

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