La thérapie cellulaire est une avenue pleine de promesses pour la régénération myocardique, par le remplacement du tissu nécrosé, ou en prévenant l'apoptose du myocarde survivant, ou encore par l'amélioration de la néovascularisation. Les cellules souches de la moelle osseuse (CSMO) expriment des marqueurs cardiaques in vitro quand elles sont exposées à des inducteurs. Pour cette raison, elles ont été utilisées dans la thérapie cellulaire de l'infarctus au myocarde dans des études pre-cliniques et cliniques. Récemment, il a été soulevé de possibles effets bénéfiques de l'ocytocine (OT) lors d’infarctus. Ainsi, l’OT est un inducteur de différenciation cardiaque des cellules souches embryonnaires, et cette différenciation est véhiculée par la voie de signalisation du monoxyde d’azote (NO)-guanylyl cyclase soluble. Toutefois, des données pharmacocinétiques de l’OT lui attribue un profil non linéaire et celui-ci pourrait expliquer les effets pharmacodynamiques controversés, rapportés dans la lttérature. Les objectifs de ce programme doctoral étaient les suivants : 1) Caractériser le profil pharmacocinétique de différents schémas posologiques d'OT chez le porc, en développant une modélisation pharmacocinétique / pharmacodynamique plus adaptée à intégrer les effets biologiques (rénaux, cardiovasculaires) observés. 2) Isoler, différencier et trouver le temps optimal d’induction de la différenciation pour les CSMO porcines (CSMOp), sur la base de l'expression des facteurs de transcription et des protéines structurales cardiaques retrouvées aux différents passages. 3) Induire et quantifier la différenciation cardiaque par l’OT sur les CSMOp. 4) Vérifier le rôle du NO dans cette différenciation cardiaque sur les CSMOp. Nous avons constaté que le profil pharmacocinétique de l’OT est mieux expliqué par le modèle connu comme target-mediated drug disposition (TMDD), parce que la durée du séjour de l’OT dans l’organisme dépend de sa capacité de liaison à son récepteur, ainsi que de son élimination (métabolisme). D'ailleurs, nous avons constaté que la différenciation cardiomyogénique des CSMOp médiée par l’OT devrait être induite pendant les premiers passages, parce que le nombre de passages modifie le profile phénotypique des CSMOp, ainsi que leur potentiel de différenciation. Nous avons observé que l’OT est un inducteur de la différenciation cardiomyogénique des CSMOp, parce que les cellules induites par l’OT expriment des marqueurs cardiaques, et l'expression de protéines cardiaques spécifiques a été plus abondante dans les cellules traitées à l’OT en comparaison aux cellules traitées avec la 5-azacytidine, qui a été largement utilisée comme inducteur de différenciation cardiaque des cellules souches adultes. Aussi, l’OT a causé la prolifération des CMSOp. Finalement, nous avons observé que l'inhibition de la voie de signalisation du NO affecte de manière significative l'expression des protéines cardiaques spécifiques. En conclusion, ces études précisent un potentiel certain de l’OT dans le cadre de la thérapie cellulaire cardiomyogénique à base de cellules souches adultes, mais soulignent que son utilisation requerra de la prudence et un approfondissement des connaissances. / Cell therapy has been suggested as a promising treatment for myocardial regeneration through cardiomyocyte replacement or by preventing apoptosis of surviving myocardium and/or improving neovascularisation. Bone marrow stem cells (BMSCs) express cardiac markers in vitro upon stimulation with different inducers. The BMSCs have been used as cell therapy after myocardial infarction (MI) in pre-clinical and clinical studies. Recent reports have uncovered the potential beneficial effects of oxytocin (OT) after MI. Particularly, OT is an inducer of cardiomyogenic differentiation of embryonic stem cells and this differentiation is mediated by the nitric oxide (NO)-soluble guanylyl cyclase pathway. However, some studies have shown that OT exhibits nonlinear pharmacokinetics and that this could explain the previously described controversial hemodynamic alterations. Therefore the objectives of the present work were to: 1) Characterize the pharmacokinetic profile of different dosing regimens of OT in swine, by using a more suitable pharmacokinetic / pharmacodynamic modelization that could explain the time-course of cardiovascular and renal effects observed following OT administration. 2) To isolate, differentiate and find the optimum time of porcine BMSC (pBMSC) differentiation based on the expression of cardiac related transcription factors and structural proteins expressed at different passages. 3) To induce and quantify the OT-mediated cardiomyogenic differentiation of pBMSCs. 4) To document the role of the NO pathway in the OT-mediated cardiomyogenic differentiation of pBMSCs. We found that OT pharmacokinetics are better explained by target-mediated drug disposition (TMDD) kinetics, because the time-course of plasma OT concentration depends on the binding capacity to its receptor, as well as OT elimination (metabolism). Also, we found that OT-mediated cardiomyogenic differentiation of pBMSCs should be induced during the first passages, because passaging affects the phenotypic profile of pBMSCs, as well as the differentiation potential of pBMSCs. We observed that OT induces cardiomyogenic differentiation of pBMSCs, because OT-induced cells expressed cardiac markers, and the expression of cardiac specific proteins was more abundant in OT-treated cells vs. 5-azacytidine-treated cells, which has been used widely as a cardiomyogenic differentiation inducer of adult stem cells. Moreover, OT improved proliferation of pBMSCs. Finally, we observed that the inhibition of the NO pathway significantly affects the expression of cardiac specific proteins. To conclude, these studies demonstrate some interesting potential in cardiomyogenic differentiation of adult stem cells for OT, but its precise role in cell therapy will need prudence and further investigations.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

A circulação extracorpórea com hipotermia (CEC-H) é um procedimento comumente utilizado em cirurgias cardíacas, que representa um fator de risco para o paciente por promover extensa hemodiluição e profundas alterações fisiológicas. Nestas cirurgias, utiliza-se a cefuroxima como antimicrobiano para profilaxia de infecções, estando sua concentração inibitória mínima (CIM90) na faixa de 4 a 16 µg/mL dependendo da espécie e cepa bacteriana. Vários esquemas posológicos tem sido propostos para a profilaxia com este antimicrobiano. Assim, o objetivo do presente estudo foi investigar a farmacocinética e a disponibilidade sistêmica da cefuroxima, administrada I.V., bolus, na dose de 1,5g a 17 pacientes submetidos à cirurgia cardíaca com ou sem CEC-H. Desenvolveu-se método analítico simples seletivo e sensível em CLAE-UV para determinar a cefuroxima no plasma e tecido subcutâneo destes pacientes. Os resultados evidenciaram que independente das alterações causadas pela CEC-H, obtiveram-se baixas concentrações plasmáticas, inferiores ao CIM90, a partir da 9a hora após a administração da medicação nos dois grupos de pacientes investigados. Esta baixa disponibilidade sistêmica da cefuroxima após administração de 1,5 g pode favorecer o desenvolvimento de infecções pós-cirúrgicas e o desenvolvimento de cepas bacterianas resistentes. Por outro lado, a disposição cinética da cefuroxima foi alterada pela CEC-H, evidenciando-se ligeiro mas significativo prolongamento da meia vida biológica e redução da depuração plasmática nos pacientes submetidos a este procedimento. A ausência de alterações no volume de distribuição está de acordo com a penetração do antibiótico no tecido, uma vez que a quantidade de cefuroxima presente no subcutâneo foi comparável em ambos os grupos de pacientes investigados. Os dados obtidos permitem recomendar mudanças no regime posológico para manter níveis plasmáticos adequados e garantir a profilaxia com cefuroxima. / Cardiopulmonary bypass and hypothermia (HCPB) is a procedure commonly used during heart surgery, representing a risk factor for the patient by promoting extensive hemodilution and profound physiological changes. Cefuroxime is used for the prophylaxis of infection after heart surgery and its minimum inhibitory concentration (MIC90) may vary from 4 to 16 µg/mL depending on the bacterial species and strain. Several dose schemes have been suggested for prophylaxis with this antimicrobial agent. Thus, the objective of the present study was to assess in a comparative manner the systemic availability of cefuroxime administered intravascularly at the dose of 1.5 g in bolus to 17 patients submitted to heart surgery with or without HCPB. An improved, simple, selective and sensitive micromethod based on HPLC-UV is described to determine cefuroxime in plasma and fat tissue. Despite the differences recorded during the study period as a consequence of HCPB, antibiotic concentrations lower than MIC90 were obtained as early as after the 9th h for the surgical patients of the two groups of patients investigated. Thus, the low systemic availability of cefuroxime after the administration of a 1.5 g dose may be the factor responsible for postoperative infections and may favor the development of resistant bacterial strains. By the other hand, cefuroxime kinetic disposition was altered by HCPB showing a slight prolongation of biological half-life e reduction of plasma clearance. Unchanged apparent volume of distribution was according antibiotic tissue penetration since in both groups of patients the amount of cefuroxime obtained was comparable. The data obtained permit us to recommend a change in the dose scheme in order to maintain adequate plasma levels of the drug and thus guarantee prophylaxis with cefuroxime.

Tuberculosis, the leading cause of death by a single infection disease caused by bacteria, requires long treatments and the bacteria are prone to develop drug resistance. Therefore, new efficient treatment regiments needs developing, which requires new tools for drug development. A major reason for discontinuance of a drug under development is undesired pharmacokinetic properties. Therefore, it is important to have early information of this, preferably the first time the drug is tested in animals. The first in vivo pharmacokinetic experiment is often done in mice and the only information present at this stage are often in vitro values and physicochemical properties. Physiological-based pharmacokinetic modelling can be used to extrapolate from in vitro to in vivo values. From this, the first in vivo pharmacokinetic experiment can be designed, often with the goal of reducing the amount of mice. This goal is one of the three R.s and it is called Reduction. To explore the Reduction of an experiment population pharmacokinetic modelling can be utilized via exploration of the imprecision, bias and probability of an informative experiment to evaluate if a design meets the goal of Reduction. In this report a recommendation of the first in vivo pharmacokinetic experiment is presented. This is based on in vitro values and physicochemical properties that are common in anti-tuberculosis drugs. If the probability of an informative experiment is critical, a terminal sampling of 40 mice is recommended. If imprecision and bias are necessary, zipper sampling of 10 mice is recommended.

This dissertation deals with quantitative perfusion analysis of MRI contrast-enhanced image time sequences. It focuses on two so far separately used methods -- Dynamic contrast-enhanced MRI (DCE-MRI) and Dynamic susceptibility contrast MRI (DSC-MRI). The common problem of such perfusion analyses is the unreliability of perfusion parameters estimation. This penalizes usage of these unique techniques on a regular basis. The presented methods are intended to improve these drawbacks, especially the problems with quantification in DSC in case of contrast agent extravasation and instability of the deconvolution process in DCE using advanced pharmacokinetic models. There are a few approaches in literature combining DCE and DSC to estimate new parameters of the examined tissue, namely the relaxivity of the vascular and of the interstitial space. Originally, in this scheme, the 2CXM DCE model was used. Here various models for DCE analysis are tested keeping in mind the DCE-DSC combination. The ATH model was found to perform better in this setting compared to 2CXM. Finally, the ATH model was used in alternating DCE-DSC optimization algorithm and then in a truly fully simultaneous DCE-DSC. The processing was tested using simulated and in-vivo data. According to the results, the proposed simultaneous algorithm performs better in comparison with sequential DCE-DSC, unleashing full potential of perfusion analysis using MRI.

La biosurveillance humaine consiste en des mesures de produits chimiques ou de leurs métabolites dans des liquides biologiques. Ces données biologiques sont souvent interprétées en les comparant à des valeurs dites bio-équivalentes aux valeurs toxicologiques de référence (VTR) qui ont été pour la plupart définies grâce à l’utilisation de modèles animaux dans un contexte de simple exposition chimique. Pourtant, elles peuvent résulter de co-expositions multivoies (cas des composés organiques volatils (COVs)) pouvant donner lieu à des interactions toxicocinétiques chez humain. Des approches de modélisation toxicocinétique à base physiologique (TCBP) ont été conçues pour étudier ces interactions. Mais, leur impact sur la variabilité interindividuelle (VI) de la toxicocinétique des substances individuelles, et l’évaluation résultante du risque toxique des contaminants chimiques suite à une exposition multivoies, n’ont que peu ou pas été investigués. Par ailleurs, des études proposent une approche de reconstitution directe de l’exposition chimique externe à partir de mesures sanguines de COVs (composés parents) grâce à des modèles TCBP probabilistes, souvent construits pour des adultes de 70 kg, et des calculs de probabilité. C’est la dosimétrie inverse. Mais les incertitudes associées aux estimations d’exposition externe faites grâce à cette approche à partir de mesures biologiques ponctuelles collectées lors des enquêtes de santé n’ont presque pas été étudiées. La présente recherche doctorale vise à caractériser l’impact des co-expositions chimiques multivoies sur la variabilité interindividuelle de la toxicocinétique des COVs, en vue d’en tenir éventuellement compte dans la mise au point dans cette thèse d’approches appliquées de dosimétrie inverse. Dans un premier temps, nous avons construit des modèles TCBP multivoies pour deux mélanges (benzène, toluène, éthylbenzène et m-xylène (BTEX) d’une part, et trichloroéthylène et chlorure de vinyle (TCE-CV) d’autre part) pour des sous-populations humaines d’âges différents (y compris une sous-population d’adultes). Ces modèles ont été couplés à des simulations de Monte Carlo pour explorer l’impact des co-expositions multivoies sur la VI de la toxicocinétique des substances individuelles en cas d’expositions ‘’faibles’’ ou ‘’élevées’’. Des index de variabilité (IV) ont été calculés comme étant le rapport du 95 ème centile de la distribution d’une dose interne chez les autres sous-populations étudiées au 50 ème centile de la même distribution chez les adultes. Dans un deuxième temps, nous avons raffiné l’approche existante de dosimétrie inverse en développant des modèles TCBP probabilistes d’inhalation pour des sous-populations canadiennes (d’âge, de poids corporel et de taille différents) dont les mesures sanguines de toluène ont été collectées lors du cycle 3 de l’enquête canadienne sur les mesures de la santé (ECMS-3), en vue de reconstituer leur exposition externe correspondante. Enfin, nous avons développé une approche individuelle de dosimétrie inverse pour estimer l’exposition externe au toluène à partir des mesures urinaires d’un de ses métabolites (l’acide S-benzylmercapturique, ou en anglais : S-benzylmercapturic acid ou BMA) rapportées chez des individus Canadiens. Ici, deux techniques ont été testées pour cette estimation : estimer l’exposition au toluène à partir des mesures ponctuelles de BMA urinaire d’une journée complète obtenues chez chaque individu et estimer l’exposition à partir d’une mesure individuelle de BMA urinaire sur des urines de 24 h. L’approche individuelle nous a permis de proposer une méthode pour quantifier l’incertitude, c’est-à-dire l’erreur possible, sur les estimations d’exposition externe faites par dosimétrie inverse à partir des mesures ponctuelles provenant des enquêtes de santé. Cette étude doctorale a révélé que l’impact des co-expositions multivoies sur la VI toxicocinétique peut dépendre des composés des mélanges et du niveau d’exposition à ces substances. Par exemple, la variation obtenue sur les IVs basés sur la quantité de substance métabolisée par les CYP2E1 est d’environ -9 à -5 % et -38 à -33% pour le benzène respectivement pour les expositions ‘’faibles’’ et ‘’élevées’’ simulées au mélange. Pour le CV et le TCE, elle est respectivement de -17 à -13% et -20 à -11% pour les expositions ‘’élevées’’, et nulle pour les ‘’faibles’’ expositions au mélange. Les expositions au toluène dans l’air estimées par dosimétrie inverse dans cette thèse (médianes entre 0,004 et 0,01 ppm) sont bien en dessous des valeurs guides maximales recommandées par Santé Canada pour une exposition chronique et suggèrent une exposition via l’air intérieur. L’incertitude mentionnée plus haut, quant à elle, varie entre 15 et 23 % dans le cadre de nos travaux. La présente étude doctorale a contribué à améliorer l’évaluation du risque toxicologique des COVs. / Human biomonitoring consists in the measurements of chemicals or their metabolites in biological matrices. These biological data are often interpreted by comparison with so-called bio-equivalent values to the toxicological reference values (TRV) which have for the most part been defined through the use of animal models in a context of simple chemical exposure. However, biomonitoring data can result from multi-routes co-exposures to multiple chemical such as Volatile Organic Compounds (VOCs), which can give rise to toxicokinetic interactions in the human body. Physiologically-based pharmacokinetic (PBPK) modeling approaches have been developed to study these interactions. But, their impact on the interindividual variability (IV) of the toxicokinetics of individual substances, and the evaluation of the toxic risk of chemical contaminants, that may result from multi-routes exposure, have only been sparsely studied. Further, the scientific literature suggests an approach for the direct reconstruction of external chemical exposure from blood measurements of VOCs’ parent compounds. This is generally done for 70-kg adults by the use of appropriate PBPK models, combined with a probability calculation approach, in a process called “reverse dosimetry”. But the uncertainties associated with estimates of external exposure made using this approach from biological spot measurements collected during health surveys have hardly been studied. The current doctoral research aims to characterize the impact of multi-routes chemical co-exposures on the interindividual variability of toxicokinetics, in order to account it for in the development in this thesis of applied approaches of reverse dosimetry. First, we built multi-routes probabilistic PBPK models for two mixtures (benzene, toluene, ethylbenzene and m-xylene (BTEX) on one hand, and trichloroethylene and vinyl chloride (TCE-VC) on the other hand) for human subpopulations of different ages (including one of adults). These models were coupled with Monte Carlo simulations in order to explore the impact of multi-routes co-exposures on the IV of the toxicokinetics of individual compounds at ‘low’ or ‘high’ exposures. Variability indices (VIs) were calculated as the ratio of the 95th percentile value of the distribution of an internal dose in the other subpopulations studied to the 50th percentile value of the same distribution in adults. In a second step, we refined the existing reverse dosimetry approach by developing probabilistic inhalation PBPK models for Canadian subpopulations (of different age, body weight and size) whose blood toluene measurements were collected during the third cycle of Canadian Health Measures Survey (CHMS-3), in order to reconstruct their corresponding external exposure. Finally, we have developed an individual reverse dosimetry approach to estimate external exposure to toluene from urinary measurements of one of its metabolites (S-benzylmercapturic acid or BMA) reported in Canadian individuals. Two techniques were tested here for this estimation: estimating toluene exposure from spot measurements of urinary BMA of a full day obtained in each individual and estimating exposure from an individual measurement of urinary BMA performed on 24-h urines. The individual approach allowed us to propose a method to quantify the uncertainty, that means the possible error, on the estimates of external exposure made by reverse dosimetry from spot measurements from health surveys. This doctoral study revealed that the impact of multi-routes co-exposures on IV of toxicokinetics may depend on the compounds in the mixtures and the level of exposure to these substances. For example, the variation obtained on the amount of substance metabolized by CYP2E1-based VIs based is about -9 to -5% and -38 to -33% for benzene respectively for 'low' and 'high' exposures simulated to the mixture. For VC and TCE, it is respectively about -17 to -13% and -20 to -11% for "high" exposures, and zero for "low" exposures to the mixture. The exposures to toluene in air estimated by reverse dosimetry in this thesis (median between 0.004 and 0.01 ppm) are well below the maximum guideline values recommended by Health Canada for chronic exposure and suggest an exposure of Canadian studied via indoor air. The uncertainty mentioned above varies between 15 and 23% in the context of our work. The present doctoral study has contributed to improving the assessment of the toxicological risk of VOCs.

Infusion pumps administer medications like morphine to pediatric patients in order to manage pain. Drug delivery delays can be the result of flow rate variabilities in the infusion pump system. Due to the risk of over-or underdosing, this could have a high impact on the pediatric population. This study’s aim is to investigate the effect of drug dilution and dosing delays by investigating which factors affect the morphine concentration in the patient. Implementation of a previously developed population pharmacokinetic model was performed in MATLAB. Then combining it with a self-developed model of the infusion pump system, a model which included the infusion pump and the system between the pump and the patient. Simulations were performed to investigate the contributing factors. The results show that dosing delays decrease with an increasing patient’s age. There are larger morphine concentration variations with lower syringe flow rates. A decrease in dosage and a smaller syringe volume result in a shorter time of reaching a steady state concentration. Using the wrong syringe which is not compatible with the machine will lead to an increasing morphine concentration in the patient that does not reach a steady state. A limitation of the study was that no clinical data was used for the simulations. These results are useful for clinicians when making decisions regarding intravenous administration of morphine, potentially leading to fewer medication errors. / Infusionspumpar administrerar läkemedel som morfin till pediatriska patienter för smärtlindring. Fördröjning av läkemedelstillförsel kan vara resultatet av flödeshastighetsvariationer i infusionspumpsystemet. På grund av risken för över- eller underdosering kan detta ha en stor inverkan på den pediatriska populationen. Denna studies syfte är att undersöka effekten av läkemedels- utspädning och -fördröjning genom att undersöka vilka faktorer som påverkar koncentrationen av morfin i patienten. Implementering av en tidigare utvecklad populationsfarmakokinetisk modell gjordes i MATLAB . För att sedan kombinera den med en egenutvecklad modell av infusionspumpsystemet, en modell som inkluderade infusionspumpen och systemet mellan pumpen och patienten. Simuleringar utfördes för att undersöka de bidragande faktorerna. Resultaten visar att doseringsfördröjningar minskar med patientens stigande ålder. Det finns större koncentrationsvariationer med lägre sprutflödeshastig- heter. En minskning av dosen och en mindre sprutvolym resulterar i en kortare tid för att uppnå en steady state-koncentration. Användning av fel spruta som inte är kompatibel med maskinen kommer att leda till en ökad morfinkon- centration hos patienten som inte når ett stabilt tillstånd. En begränsning med studien var att inga klinisk data användes för simuleringarna. Dessa resultat är användbara för läkare när de fattar beslut om intravenös administrering av morfin, vilket potentiellt kan leda till färre medicineringsfel.

Outputs of dose–response assessments can be used as benchmarks that help to identify the need for risk management measures to reduce population health risks associated with exposure to chemicals. Various approaches can be used to facilitate the incorporation of chemical- or scenario-specific data into dose–response analyses, as a means of replacing or influencing default assumptions and extrapolations. The goal of the first part of this thesis was to examine the evolution of approaches to the incorporation of chemical- and scenario-specific data in dose–response assessments in regulatory settings, and identify contextual factors that serve as barriers and facilitators to the use of approaches. A main focus of the investigation was on physiological modelling, which is the most commonly-used category of approaches enabling extrapolations that depart from default assumptions. Evaluations of the dose–response applications of physiological modelling in the peer-reviewed scientific literature and in regulatory reports were conducted. Similarities between the scientific literature databases and regulatory reports were observed with respect to the evolution of physiological modelling in dose–response assessments, notably related to the timing, quantity, and annual frequency of publications. These similarities indicate that a factor in the low dose–response application of physiological modelling, relative to the overall production of physiological models, is an absence of data. However, variability in adoption of physiological modelling in regulatory dose–response assessments was observed among—and even within—organizations faced with the same data, indicating that other factors influence regulatory uptake of physiological modelling. Analysis of a survey indicated that factors acting as barriers or facilitators to regulatory risk assessors’ incorporation of increasingly data-informed approaches originated in both external and internal contexts. The external context was composed of the regulatory environment, domestic and international alignment, availability of external expertise, background of peer reviewers and stakeholders, availability and accessibility of software and tools, and chemical-dependent factors. The internal context was influenced by problem formulation, time and financial resources, organizational and management support, and training. A conceptual framework demonstrating how these factors impact a risk assessor’s ability to incorporate chemical- and scenario-specific data in dose–response analysis was developed, and subsequently used to provide recommendations on actions that could be taken to increase regulatory adoption of increasingly data-informed approaches. The second part of the thesis focused on the development of a knowledge translation tool designed to assist risk managers in the evaluation of dose–response analyses. The tool was focused on occupational exposure limits (OELs), and provides a guide to occupational hygienists in evaluating the relevance and reliability of individual OELs. When occupational hygienists are faced with multiple varying OELs for a chemical of interest, these evaluations can support the selection of the most appropriate OEL for a given situation. The usefulness of the tool was demonstrated for the selection of OELs for an OEL-rich compound (n-hexane), an OEL-poor compound (methamphetamine), and one additional compound (manganese). Such a tool can improve occupational hygienists’ understanding of the basis of OELs and the levels of protection afforded by each, which can contribute to more informed risk management decisions.

Die Phänotypisierung von Cytochrom P450 (CYP) und Leberfunktionstests sind wichtige Methoden in der Klinik. Die Methoden nutzen die Pharmakokinetik (PK) von Testsubstanzen und ihren Metaboliten, um Einblicke in die Stoffwechselkapazität der Leber und in die Aktivität von Enzymen und Transportern zu gewinnen. Die Leberfunktionstests werden nicht nur von zahlreichen Proband:innenmerkmalen, sondern auch von den Besonderheiten der Untersuchung beeinflusst. Eine zentrale Herausforderung besteht darin, die verschiedenen Faktoren, die das Ergebnis der Messungen beeinflussen, voneinander zu trennen, um ihren jeweiligen Einfluss auf das Messergebniss zu untersuchen. In dieser Arbeit wurde die Herausforderung durch Metaanalysen und physiologisch basierte Pharmakokinetik Modellierung (PBPK) angegangen. Es wurde eine offene Pharmakokinetik-Datenbank (PK-DB) entwickelt und PK-Daten für ein breites Spektrum von Testsubstanzen kuratiert. Meines Wissens enthält PK-DB derzeit den größten offenen PK-Datensatz zu Testsubstanzen. Der Datensatz ermöglichte die Identifizierung und Quantifizierung von demografischen und rassischen Bias (Geschlecht, ethnische Zugehörigkeit, Alter, Gesundheitszustand), Meldefehlern und Unstimmigkeiten in der Literatur. Auf der Grundlage der Daten wurde eine Metaanalyse der PK von Koffein im Hinblick auf verschiedene Faktoren bzgl. Leberfunktion und CYP1A2-Aktivität durchgeführt. Insbesondere wurde das vorhandene Wissen über die Auswirkungen des Rauchens, der Einnahme oraler Verhütungsmittel, verschiedener Krankheiten und Begleitmedikationen auf die PK von Koffein durch Metaanalysen und Datenintegration konsolidiert. Ebenso wurde die Messgenauigkeit der Koffeinkonzentration in Bezug auf den Messprotokol analysiert. Darüber hinaus wurde der Einfluss des CYP2D6-Polymorphismus untersucht. Hierzu wurde ein PBPK-Modell für Dextromethorphan und seine Metaboliten Dextrorphan und Dextrorphan O-Glucuronid entwickelt und mit den PK-Daten kalibriert und validiert. / Cytochrome P450 (CYP) phenotyping and dynamic liver function testing are essential methods in clinical practice. These methods utilize the pharmacokinetics (PK) of test substances and their metabolites to gain insight into the liver's metabolic capacity and the activity of enzymes and transporters. Liver function tests are not only influenced by numerous characteristics of a studied subject but also by the specifics of individual study procedures. A key challenge is to disentangle the various factors which influence the outcome of the measurements from each other to study their influence on the dynamic liver function and CYP phenotype. In this work, the challenge was addressed through meta-analysis and physiologically based pharmacokinetic modeling. As a foundation, an open pharmacokinetics database was developed and pharmacokinetics data were curated for a wide range of test substances. To my knowledge, PK-DB currently contains the largest open pharmacokinetic dataset on substances used for phenotyping and dynamical liver function testing. The dataset allowed for identifying and quantifying demographic and racial bias (sex, ethnicity, age, health), reporting errors, and inconsistencies in pharmacokinetic literature. Based on the data, a caffeine pharmacokinetics meta-analysis was conducted concerning various factors affecting liver function and CYP1A2 activity. In particular, meta-analysis and data integration solidified existing knowledge on the effects of smoking, oral contraceptives, multiple diseases, and co-medications on caffeine pharmacokinetics. Similarly, the measurement accuracy of caffeine concentration was investigated with respect to various aspects of the measurement protocol. In addition, the impact of CYP2D6 polymorphism was investigated. Therefore, a PBPK model of dextromethorphan (DXM) and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) was developed, and calibrated, and validated with pharmacokinetics data.

Le méthylphénidate est un des médicaments les plus prescrits pour les patients ayant un trouble déficitaire de l’attention (TDAH). Comme la réponse au méthylphénidate peut varier d’un patient à l’autre, l’optimisation de la dose passe souvent par une période de titration. Au cours de cette titration, le clinicien, guidé par son expertise, prescrit différents niveaux de dose jusqu’à trouver celle qui convienne au patient. Ceci en fait un processus lourd pour le patient. L’individualisation des doses de méthylphénidate peut donc être améliorée par l’utilisation d’approches pharmacométriques. Ces approches cristallisent les informations connues sur le médicament dans un langage condensé basé sur les mathématiques et statistiques. Ainsi, leur utilisation dans le contexte du méthylphénidate fournit un outil numérique permettant de comprendre sa pharmacocinétique (ce que le corps fait au méthylphénidate) et sa pharmacodynamie (ce que le méthylphénidate fait au corps). Cette thèse se met à la quête de l’enrichissement de ces approches pharmacométriques en trois volets. La première problématique abordée concerne la grande variabilité interindividuelle dans le traitement du méthylphénidate. Le début de la thèse s’attaque à l’interchangeabilité des médicaments novateurs et génériques ayant une grande variabilité interindividuelle. Une nouvelle méthode est proposée pour comparer efficacement les médicaments selon leur pharmacocinétique. Celle-ci se base sur une méthode établie qui tient compte non seulement de la réponse moyenne d’une population à un médicament, mais aussi de la variabilité interindividuelle dans cette réponse. Cette nouvelle méthode ajoute un paramètre modulable selon le médicament étudié et corrige les problèmes de permissivité des méthodes actuelles. La pharmacodynamie du méthylphénidate est étudiée dans les deuxième et troisième volets de cette thèse. Il a été rapporté que l’efficacité du méthylphénidate décroît en fin de journée, malgré des concentrations plasmatiques similaires aux premières heures d’administration. Ainsi, suite à la prise de méthylphénidate, une tolérance aigüe se développe dans une même journée. Ce phénomène, observé sur des échelles de mesure cliniques mesurant la réduction des symptômes du TDAH, a déjà été décrit par des approches pharmacométriques. La deuxième partie de cette thèse explore la présence de cette tolérance aigüe au niveau des cibles thérapeutiques du méthylphénidate : les transporteurs de dopamine et norépinéphrine. Un modèle pharmacométrique est créé, décrivant l’interaction du méthylphénidate avec les transporteurs de dopamine et de norépinéphrine. Ce modèle est utilisé pour calculer la performance de différents régimes posologiques et explore le rôle de la norépinéphrine sur les doses nécessaires pour le traitement du TDAH. Finalement, le troisième volet ajoute la pharmacodynamie sur une échelle clinique, notamment celle du score SKAMP. Grâce au modèle pharmacométrique du deuxième volet, la dernière partie de cette thèse cherche à répondre à la question : comment l’interaction du méthylphénidate avec les transporteurs de dopamine se traduit en effet clinique? Nos résultats indiquent que l’interaction avec les transporteurs se traduit partiellement en effet clinique et que la relation entre ces deux éléments est plus significative en début de journée comparativement au soir. En somme, cette thèse a exploré les différentes facettes des méthodes pharmacométriques et leur application dans les prescriptions du méthylphénidate chez les patients atteints de TDAH. Les résultats de cette recherche démontrent l’utilité des approches pharmacométriques et ouvrent la porte à une recherche plus poussée afin de guider l’individualisation du méthylphénidate. / Methylphenidate is one of the most prescribed medications for patients with attention deficit hyperactivity disorder (ADHD). Because the response to methylphenidate varies greatly among patients, dose optimization often involves a titration period. During this titration period, the clinicians, guided by their expertise, prescribes different levels of dose until they find the one that works best for the patient. This makes it a burdensome process for the patient. Individualization of methylphenidate doses can be improved by using pharmacometric approaches. These approaches crystallize the known information about the medication into a condensed language based on mathematics and statistics. Thus, their use in the context of methylphenidate provides a digital tool for understanding its pharmacokinetics (what the body does to methylphenidate) and its pharmacodynamics (what methylphenidate does to the body). This thesis seeks to enrich these pharmacometric approaches in three parts. The first part of this dissertation concerns the high interindividual variability in methylphenidate response. The beginning of the thesis tackles the interchangeability of innovative and generic drugs with high interindividual variability. A new method is proposed to effectively compare drugs based on their pharmacokinetics. This method is based on an established method that takes into account not only the average response of a population to a drug, but also the interindividual variability in that response. This new method adds a modifiable parameter depending on the drug being studied and corrects the problems of permissiveness in current methods. The pharmacodynamics of methylphenidate are studied in the second and third parts of this thesis. It has been reported that the efficacy of methylphenidate decreases at the end of the day, despite similar plasma concentrations to those in the early hours of administration. Thus, after taking methylphenidate, acute tolerance develops within the same day. This phenomenon, observed on clinical measurement scales measuring the reduction of ADHD symptoms, has already been described by pharmacometric approaches. The second part of this thesis explores the presence of this acute tolerance at the therapeutic targets of methylphenidate: dopamine and norepinephrine transporters. A pharmacometric model is created, describing the interaction of methylphenidate with dopamine and norepinephrine transporters. This model is used to calculate the performance of different dosage regimens and explore the role of norepinephrine in the doses needed for ADHD treatment. Finally, the third part adds pharmacodynamics on a macroscopic scale, particularly the clinical effect of methylphenidate. Using the pharmacometric model from the second part, the end of this thesis seeks to answer the question: how does the interaction of methylphenidate with dopamine transporters translate into clinical effects? Our results indicate that the interaction with transporters partially translates into clinical effects and that the relationship between these two elements is more significant in the morning compared to the evening. Overall, this thesis has explored the various facets of pharmacometric methods and their application in the prescriptions of methylphenidate for patients with ADHD. The results of this research demonstrate the utility of pharmacometrics approaches and open the door to further research to guide the individualization of methylphenidate.