In risk assessment of risk chemicals, variability in susceptibility in the population is an important aspect. The health hazard of a pollutant is related to the internal exposure to the chemical, i.e. the target dose, rather than the external exposure. The target dose may be calculated by physiologically based pharmacokinetic (PBPK) modeling. Furthermore, variability in target dose may be estimated by introducing variability in the physiological, anatomical, and biochemical parameters of the model. Data on these toxicokinetic model parameters may be found in the scientific literature. Since the early seventies, a large number of experimental inhalation studies of the kinetics of several volatiles in human volunteers have been performed at the National Institute for Working Life in Solna. To this day, only very limited analyses of these extensive data have been performed. A Bayesian analysis makes it possible to merge a priori knowledge from the literature with the information in experimental data. If combined with population PBPK modeling, the Bayesian approach may yield posterior estimates of the toxicokinetic parameters for each subject, as well as for the population. One way of producing these estimates is by so-called Markov-chain Monte Carlo (MCMC) simulation. The aim of the thesis was to apply the MCMC technique on previously published experimental data. Another objective was to assess the reliability of PBPK models in general by the combination of the extensive data and Bayesian population techniques. The population kinetics of methyl chloride, dichloromethane, toluene and styrene were assessed. The calibrated model for dichloromethane was used to predict cancer risk in a simulated Swedish population. In some cases, the respiratory uptake of volatiles was found to be lower than predicted from reference values on alveolar ventilation. The perfusion of fat tissue was found to be a complex process that needs special attention in PBPK modeling. These results provide a significant contribution to the field of PBPK modeling of risk chemicals. Appropriate statistical treatment of uncertainty and variability may increase confidence in model results and ultimately contribute to an improved scientific basis for the estimation of occupational health risks.

Este trabalho introduz um modelo fisiológico para o reflexo pupilar em função das condições de iluminação (Pupil Light Reflex - PLR), e um modelo baseado em imagem para deformação dos padrões da íris. O modelo para PLR expressa o diâmetro da pupila ao longo do tempo e em função da iluminação ambiental, sendo descrito por uma equação diferencial com atraso, adaptando naturalmente o tamanho da pupila a mudanças bruscas de iluminação. Como os parâmetros do nosso modelo são derivados a partir de modelos baseados em experimentos científicos, ele simula corretamente o comportamento da pupila humana para um indivíduo médio. O modelo é então estendido para dar suporte a diferenças individuais e a hippus, além de utilizar modelos para latência e velocidade de dilatação e contração. Outra contribuição deste trabalho é um modelo para deformação realista dos padrões da íris em função da contração e dilatação da pupila. Após capturar várias imagens de íris de diversos voluntários durante diferentes estágios de dilatação, as trajetórias das estruturas das íris foram mapeadas e foi identificado um comportamento médio para as mesmas. Demonstramos a eficácia e qualidade dos resultados obtidos, comparando-os com fotografias e vídeos capturados de íris reais. Os modelos aqui apresentados produzem efeitos foto-realistas e podem ser utilizados para produzir animações preditivas da pupila e da íris em tempo real, na presença de variações na iluminação. Combinados, os dois modelos permitem elevar a qualidade de animações faciais, mais especificamente, animações da íris humana. / This thesis introduces a physiologically-based model for pupil light reflex (PLR) and an image-based model for iridal pattern deformation. The PLR model expresses the pupil diameter as a function of the environment lighting, naturally adapting the pupil diameter even to abrupt changes in light conditions. Since the parameters of the PLR model were derived from measured data, it correctly simulates the actual behavior of the human pupil. The model is extended to include latency, constriction and dilation velocities, individual differences and some constrained random noise to model hippus. The predictability and quality of the simulations were validated through comparisons of modeled results against measured data derived from experiments also described in this work. Another contribution is a model for realist deformation of the iris pattern as a function of pupil dilation and constriction. The salient features of the iris are tracked in photographs, taken from several volunteers during an induced pupil-dilation process, and an average behavior of the iridal features is defined. The effectiveness and quality of the results are demonstrated by comparing the renderings produced by the models with photographs and videos captured from real irises. The resulting models produce high-fidelity appearance effects and can be used to produce real-time predictive animations of the pupil and iris under variable lighting conditions. Combined, the proposed models can bring facial animation to new photorealistic standards.

Este trabalho introduz um modelo fisiológico para o reflexo pupilar em função das condições de iluminação (Pupil Light Reflex - PLR), e um modelo baseado em imagem para deformação dos padrões da íris. O modelo para PLR expressa o diâmetro da pupila ao longo do tempo e em função da iluminação ambiental, sendo descrito por uma equação diferencial com atraso, adaptando naturalmente o tamanho da pupila a mudanças bruscas de iluminação. Como os parâmetros do nosso modelo são derivados a partir de modelos baseados em experimentos científicos, ele simula corretamente o comportamento da pupila humana para um indivíduo médio. O modelo é então estendido para dar suporte a diferenças individuais e a hippus, além de utilizar modelos para latência e velocidade de dilatação e contração. Outra contribuição deste trabalho é um modelo para deformação realista dos padrões da íris em função da contração e dilatação da pupila. Após capturar várias imagens de íris de diversos voluntários durante diferentes estágios de dilatação, as trajetórias das estruturas das íris foram mapeadas e foi identificado um comportamento médio para as mesmas. Demonstramos a eficácia e qualidade dos resultados obtidos, comparando-os com fotografias e vídeos capturados de íris reais. Os modelos aqui apresentados produzem efeitos foto-realistas e podem ser utilizados para produzir animações preditivas da pupila e da íris em tempo real, na presença de variações na iluminação. Combinados, os dois modelos permitem elevar a qualidade de animações faciais, mais especificamente, animações da íris humana. / This thesis introduces a physiologically-based model for pupil light reflex (PLR) and an image-based model for iridal pattern deformation. The PLR model expresses the pupil diameter as a function of the environment lighting, naturally adapting the pupil diameter even to abrupt changes in light conditions. Since the parameters of the PLR model were derived from measured data, it correctly simulates the actual behavior of the human pupil. The model is extended to include latency, constriction and dilation velocities, individual differences and some constrained random noise to model hippus. The predictability and quality of the simulations were validated through comparisons of modeled results against measured data derived from experiments also described in this work. Another contribution is a model for realist deformation of the iris pattern as a function of pupil dilation and constriction. The salient features of the iris are tracked in photographs, taken from several volunteers during an induced pupil-dilation process, and an average behavior of the iridal features is defined. The effectiveness and quality of the results are demonstrated by comparing the renderings produced by the models with photographs and videos captured from real irises. The resulting models produce high-fidelity appearance effects and can be used to produce real-time predictive animations of the pupil and iris under variable lighting conditions. Combined, the proposed models can bring facial animation to new photorealistic standards.

Understanding the processes that govern pre-systemic drug absorption and elimination is of high importance in pharmaceutical research and development, and clinical pharmacotherapy, as the oral route remains the most frequently used route of drug administration. The emergence of systems pharmacology has enabled the utilisation of in silico physiologically-based pharmacokinetic (PBPK) modelling and simulation (M&S) coupled to in vitro-in vivo extrapolation in order to perform extrapolation and exploratory M&S in special populations and scenarios were concerns regarding alterations in oral drug exposure may arise, such as following gastrointestinal (GI) surgery or metabolic drug-drug interactions (DDIs).Due to the multi-factorial physiological implications of bariatric surgery, resulting in the partial resection of the GI tract, the inability to rationalise and predict trends in oral drug bioavailability (Foral) following surgery present considerable pharmacotherapeutical challenges. PBPK M&S is a highly implemented approach for the prediction of DDIs. Reoccurring issues have emerged with regards to predictions of the magnitude of mechanism-based inhibition (MBI) where overestimations of DDIs have repeatedly been reported for drugs exhibiting high intestinal extraction. The aim of this thesis was to explore the interplay between oral drug absorption and metabolism occurring in the GI tract through the exploration of the impact of bariatric surgery on oral drug exposure and by theoretically examining the nesting and hierarchy of enterocyte and enzyme turnover and its impact on MBIs in the small intestine. This would be carried out by utilising a systems pharmacology PBPK M&S approach under a general model development framework of identification and characterisation of critical intrinsic factors and parameters, model implementation and validation. Developed post bariatric surgery PBPK models allow a framework to theoretically explore physiological mechanisms associated with altered oral drug exposure pre to post surgery, which could be assigned to the interplay between dissolution, absorption and gut-wall metabolism, where dissolution and formulation properties emerged as the perhaps most important parameters in predicting the drug disposition following surgery. Model validation identified missing critical factors that are essential for additional model refinement. Developed post bariatric surgery PBPK models have the potential of aiding clinical pharmacotherapy and decision-making following surgery. A mechanistic PBPK model was developed to describe the hierarchical dependency of enzyme and enterocyte turnover in the small intestine. Predicted enzyme recovery using the nested enzyme-within-enterocyte turnover model may potentially account for reported overpredictions of mechanism-based inhibition. Developed models in this thesis showcase the advantage of PBPK M&S in the extrapolation of oral drug exposure to special population and the potential of a PBPK approach in understanding underlying the underlying mechanism governing Foral and additionally highlight the need for generation of interdisciplinary data to support model development.

Charles University Faculty of Pharmacy in Hradec Kr'alov'e Department of Biophysics and Physical Chemistry Candidate: Yestay Rakhimov Supervisor: doc. Erik Jurjen Duintjer Tebbens, Ph.D. Title of diploma thesis: Mathematics and implementations of physiologically based phar- macokinetic modeling The thesis addresses some basic aspects of pharmacokinetic modeling, which is used to describe pharmacokinetic processes. Understanding these processes is important for example to determine optimal concentrations of drugs dosing. The thesis focuses on mathematical proofs of a number of pharmacokinetic equa- tions, which are often not given in standard books. The derived equations are illustrated with numerical experiments for a particular drug in the software PharmCalcCl and MAT- LAB. 4

<p>Autoinjectors are pen-like devices that typically deliver drug products of 2 mL or less. They shield the needle before and after use, reducing patient anxiety from needle phobia and mitigating the risk of needlestick injuries and accidental contamination. Additionally, automatic delivery ensures more consistent needle penetration depth and injection force than manual injection methods. </p> <p><br></p> <p>To optimize autoinjector design, this thesis presents experimentally validated computational models that describe the processes of needle insertion, drug delivery, and transport of subcutaneously administered therapeutic proteins in the body. A multi-objective optimization framework is also proposed to guide the design of autoinjectors.</p> <p><br></p> <p>This thesis focuses on spring-driven autoinjectors, the most common type of autoinjector. It begins with an overview of the interactions between the spring-driven autoinjector, tissue, and therapeutic proteins. Moving on to Chapter 2, a computational model is presented to accurately predict the kinematics of the syringe barrel and plunger during the needle insertion process.</p> <p><br></p> <p>In Chapter 3, we present a quasi-steady model for the drug delivery process, which considers the rheology of therapeutic proteins. The Carreau model is adopted to describe protein viscosity, and explicit relationships between flow rate and pressure drop in the needle are derived. Furthermore, the applicable regime for the power-law model for protein viscosity is identified.</p> <p><br></p> <p>Chapter 4 quantifies the impact of sloshing and cavitation on therapeutic proteins in the syringe. Additionally, a workflow is presented to integrate available simulation tools to predict the performance of spring-driven autoinjectors. The influence of each design parameter of spring-driven autoinjectors on their performance is also discussed. </p> <p><br></p> <p>The spring-driven autoinjector delivers therapeutic proteins through subcutaneous administration. To gain insights into the transport process of therapeutic proteins, Chapter 5 presents a physiologically-based pharmacokinetic model that has been validated against experimental data for humans and rats. The lymph flow rate significantly affects the bioavailability of therapeutic proteins. This finding highlights the importance of studying the transport of therapeutic proteins in the lymphatic system in future research.</p> <p><br></p> <p>Chapter 6 provides a multi-objective design optimization framework for the spring-driven autoinjector. The computational model is replaced with an accurate deep neural network surrogate to improve the computational efficiency.  Using this surrogate model, we conduct a sensitivity analysis to identify essential design parameters. After that, we perform multi-objective optimization to find promising design candidates.</p> <p><br></p> <p>Chapter 7 presents a model for bubble dynamics in a protein solution. An explicit expression for the bubble dissolution rate is derived, enabling extraction of the interfacial properties of the protein-coated interface from the measured bubble radii. Moreover, analytical solutions for the response of a protein-coated bubble to an imposed acoustic pressure are derived. This work provides insight into protein-coated bubbles, which are used as vehicles to deliver drugs, as active miniature tracers to probe the rheology of soft and biological materials, or as contrast agents to enhance the ultrasound backscatter in ultrasonic imaging.</p> <p><br></p> <p>At last, in Chapter 8, we introduce a model for laser-induced cavitation that considers several key factors, such as liquid compressibility, heat transfer, and non-equilibrium evaporation and condensation. Our model's predictions for the time-course of bubble radii have been validated with experimental data. Moreover, our model reveals that the reduction of the bubble's oscillation amplitude is primarily due to a decrease in the number of vapor molecules inside the bubble, highlighting the crucial role of phase change in laser-induced cavitation bubbles.</p> <p><br></p> <p>The developed computational models and framework provide crucial insights into the development of spring-driven autoinjectors and cavitation bubbles. These studies can also enhance the efficacy and safety of the delivery of therapeutic proteins, ultimately improving patient outcomes.</p>

No description available.

Paracetamol är ett vanligt använt läkemedel med analgesisk och antipyretisk effekt. Läkemedlet finns tillgängligt i ett flertal beredningsformer och doseringsstyrkor för användning både receptfritt och i sjukhusvården. Syftet med detta projekt var att undersöka påverkan av alternativ, off-label, dosering av paracetamol i pediatrisk vård, med hjälp av fysiologiskt baserad farmakokinetisk (PBPK) modellering. Modellen utvecklades först för en vuxen population genom integrering av in vitro, in vivo och in silico data för paracetamol. Efter detta extrapolerades concentrationskurvor till en pediatrisk population med hjälp av ontogeni-information. Modellen validerades i både vuxna och barn, och var tillförlitlig för både peroral och intravenös dosering. Efter valideringen utfördes simuleringar för nio olika åldersgrupper baserat på rekommenderade doseringsprotokoll i Sverige. Simuleringarna visade att perorala tablettdoseringen var jämförbar med formulering i lösningsform, med snarlika maximumkoncentrationer och area-under-kurvan (AUC) för exponering. Hastigheten av magtömning influerade maximumkoncentrationer men inte AUC. Ytterligare testades modellens förmåga att prediktera plasmakoncentrationer i blodet efter överdosering med paracetamol. Dessa prediktioner fungerade bättre när läkemedelsmetaboliserande enzymer lämnades oförändrade, eller ökade något i aktivitet. Slutligen, den utvecklade PBPK-modellen kan användas för att säkert undersöka olika doseringsprotokoll och för design av pediatriska kliniska studier. / Paracetamol, a widely used analgesic and antipyretic drug, can be found in various formulations and doses for both home and hospital use. The aim of this study was to investigate the impact of off-label dosing of paracetamol in pediatric clinical practice using physiologically based pharmacokinetic (PBPK) modeling. The model was initially developed for adults by integrating relevant in vitro, in vivo and in silico data of paracetamol, after which the model was extrapolated for pediatrics by adding ontogeny information. The model was successfully validated in both adult and pediatric populations, and it showed accuracy for both oral and intravenous administration routes. After validation, simulations were conducted across nine different age groups following the recommended doses in Sweden. These simulations showed that tablet dose is comparable to solution dosing, resulting in nearly identical maximum concentrations and area under the curve (AUC) values. Furthermore, it was observed that gastric emptying time, which reflects the fed state of individuals, significantly influences the maximum concentration, with longer gastric emptying times resulting in lower and delayed peak concentrations. However, the gastric emptying time had no effect on the AUC values. Lastly, the model’s performance on overdose data was evaluated, and it turned out that it performs better when liver enzymes were not affected, or they were only slightly elevated. Finally, the developed PBPK model can be further used for safe and effective way of exploring dose banding and designing clinical trials in pediatrics.

Les propriétés pharmacocinétiques d’un nouveau médicament et les risques d’interactions médicamenteuses doivent être investigués très tôt dans le processus de recherche et développement. L’objectif principal de cette thèse était de concevoir des approches prédictives de modélisation du devenir du médicament dans l’organisme en présence et en absence de modulation d’activité métabolique et de transport. Le premier volet de recherche consistait à intégrer dans un modèle pharmacocinétique à base physiologique (PBPK), le transport d’efflux membranaire gouverné par les glycoprotéines-P (P-gp) dans le cœur et le cerveau. Cette approche, basée sur des extrapolations in vitro-in vivo, a permis de prédire la distribution tissulaire de la dompéridone chez des souris normales et des souris déficientes pour les gènes codant pour la P-gp. Le modèle a confirmé le rôle protecteur des P-gp au niveau cérébral, et a suggéré un rôle négligeable des P-gp dans la distribution tissulaire cardiaque pour la dompéridone. Le deuxième volet de cette recherche était de procéder à l’analyse de sensibilité globale (ASG) du modèle PBPK précédemment développé, afin d’identifier les paramètres importants impliqués dans la variabilité des prédictions, tout en tenant compte des corrélations entre les paramètres physiologiques. Les paramètres importants ont été identifiés et étaient principalement les paramètres limitants des mécanismes de transport à travers la membrane capillaire. Le dernier volet du projet doctoral consistait à développer un modèle PBPK apte à prédire les profils plasmatiques et paramètres pharmacocinétiques de substrats de CYP3A administrés par voie orale à des volontaires sains, et de quantifier l’impact d’interactions médicamenteuses métaboliques (IMM) sur la pharmacocinétique de ces substrats. Les prédictions des profils plasmatiques et des paramètres pharmacocinétiques des substrats des CYP3A ont été très comparables à ceux mesurés lors d’études cliniques. Quelques écarts ont été observés entre les prédictions et les profils plasmatiques cliniques mesurés lors d’IMM. Cependant, l’impact de ces inhibitions sur les paramètres pharmacocinétiques des substrats étudiés et l’effet inhibiteur des furanocoumarins contenus dans le jus de pamplemousse ont été prédits dans un intervalle d’erreur très acceptable. Ces travaux ont contribué à démontrer la capacité des modèles PBPK à prédire les impacts pharmacocinétiques des interactions médicamenteuses avec une précision acceptable et prometteuse. / Early knowledge of pharmacokinetic properties of a new drug candidate and good characterization of the impact of drug-drug interaction (DDI) on those properties is of crucial importance in the process of drug research and development. The main objective of this thesis consisted in the conception of PBPK models able to predict the drug disposition in the absence and presence of metabolic and transport activity modulation. The first part of this work aimed to develop a PBPK model that incorporates the efflux function of P-gp expressed in various tissues, in order to predict the impact of P-gp activity modulation on drug distribution. This approach, based on in vivo-in vitro extrapolation for estimating the transport-related parameters, allowed the prediction of domperidone distribution in heart and brain of wild-type mice and P-gp deficient mice. The model pointed out the protective function of P-gp in brain whereas it showed the negligible protective effect of P-gp in heart. The second part of the project aimed to perform the global sensitivity analysis of the previous PBPK model, in order to investigate how the uncertainly and variability of the correlated physiological parameters influence the outcome of the drug distribution process. While a moderate variability of the model predictions was observed, this analysis confirmed the importance for a better quantitative characterization of parameters related to the transport processes trough the blood-tissue membrane. Accounting for the input correlation allowed the delineation of the true contribution of each input to the variability of the model outcome. The last part of the project consisted in predicting the pharmacokinetics of selected CYP3A substrates administered at a single oral dose to human, alone or with an inhibitor. Successful predictions were obtained for a single administration of the CYP3A substrates. Some deviations were observed between the predictions and in vivo plasma profiles in the presence of DDI. However, the impact of inhibition on the PK parameters of the selected substrates and the impact of grapefruit juice-mediated inhibition on the extent of intestinal pre-systemic elimination were predicted within a very acceptable error range. Overall, this thesis demonstrated the ability of PBPK models to predict DDI with promising accuracy.

It is believed that the extremely hot European summer in 2003, where tens of thousands died in buildings, will become the norm by the 2040s, and hence there is the urgent need to accurately assess the risk that buildings pose. Thermal simulations based on warmer than typical years will be key to this. Unfortunately, the existing warmer than typical years, such as probabilistic Design Summer Years (pDSYs) are not robust measures due to their simple selection method, and can even be cooler than typical years. This study developed two new summer reference years: one (pHSY-1) is suitable for assessing the occurrence and severity of overheating while the other (pHSY-2) is appropriate for evaluating the thermal stress. Both have been proven to be more robust than the pDSYs. In addition, this study investigated the spatial variation in overheating driven by variability in building characteristics and the local environment. This variation had been ignored by previous studies, as most of them either created thermal models using building archetypes with little or no concern about the influence of local shading, or assumed little variation in climate across a landscape. For the first time, approximately a thousand more accurate thermal models were created for a UK city based on the remote measurement including building characteristics and their local shading. By producing overheating and mortality maps this study found that spatial variation in the risk of overheating was considerably higher due to the variability of vernacular forms, contexts and climates than previously thought, and that the heat-related mortality will be tripled by the 2050s if no building and human thermal adaptations are taken. Such maps would be useful to Governments when making cost-effective adaptation strategies against a warming climate.