One of the major challenges faced by the pharmaceutical industry is to accelerate the product innovation process and reduce the time-to-market for new drug developments. This involves billions of dollars of investment due to the large amount of experimentation and validation processes involved. A computational modeling approach, which could explore the design space rapidly, reduce uncertainty and make better, faster and safer decisions, fits into the overall goal and complements the product development process. Our research focuses on the early preclinical stage of the drug development process involving lead selection, optimization and candidate identification steps. Our work helps in screening the most favorable candidates based on the biopharmaceutical and pharmacokinetic properties. This helps in precipitating early development failures in the early drug discovery and candidate selection processes and reduces the rate of late-stage failures, which is more expensive. In our research, we successfully integrated two well-known models, namely the drug release model (dissolution model) with a drug transport model (compartmental absorption and transit (CAT) model) to predict the release, distribution, absorption and elimination of an oral drug through the gastrointestinal (GI) tract of the human body. In the CAT model, the GI tract is envisioned as a series of compartments, where each compartment is assumed to be a continuous stirred tank reactor (CSTR). We coupled the drug release model in the form of partial differential equations (PDE's) with the CAT model in the form of ordinary differential equations (ODE's). The developed model can also be used to design the drug tablet for target pharmacokinetic characteristics. The advantage of the suggested approach is that it includes the mechanism of drug release and also the properties of the polymer carrier into the model. The model is flexible and can be adapted based on the requirements of the clients. Through this model, we were also able to avoid depending on commercially available software which are very expensive. In the drug discovery and development process, the tablet formulation (oral drug delivery) is an important step. The tablet consists of active pharmaceutical ingredient (API), excipients and polymer. A controlled release of drug from this tablet usually involves swelling of the polymer, forming a gel layer and diffusion of drug through the gel layer into the body. The polymer is mainly responsible for controlling the release rate (of the drug from the tablet), which would lead to a desired therapeutic effect on the body. In our research, we also developed a molecular design strategy for generating molecular structures of polymer candidates with desired properties. Structure-property relationships and group contributions are used to estimate the polymer properties based on the polymer molecular structure, along with a computer aided technique to generate molecular structures of polymers having desired properties. In greater detail, we utilized group contribution models to estimate several desired polymer properties such as grass transition temperature (Tg), density (ρ) and linear expansion coefficient (α). We subsequently solved an optimization model, which generated molecular structures of polymers with desired property values. Some examples of new polymer repeat units are - [CONHCH₂ - CH₂NHCO]n -, - [CHOH - COO]n -. These repeat-units could potentially lead to novel polymers with interesting characteristics; a polymer chemist could further investigate these. We recognize the need to develop group contribution models for other polymer properties such as porosity of the polymer and diffusion coefficients of water and drug in the polymer, which are not currently available in literature. The geometric characteristics and the make-up of the drug tablet have a large impact on the drug release profile in the GI tract. We are exploring the concept of tablet customization, namely designing the dosage form of the tablet based on a desired release profile. We proposed tablet configurations which could lead to desired release profiles such as constant or zero-order release, Gaussian release and pulsatile release. We expect our work to aid in the product innovation process. / Ph. D.

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.

Malaria is the most important parasitic disease in man and it kills approximately 2,000 people each day. Pregnant women are especially vulnerable to malaria with increased incidence and mortality rates. There are indications that pregnancy alters the pharmacokinetic properties of many antimalarial drugs. This is worrisome as lower drug exposures might result in lowered efficacy and lower drug exposures can also accelerate the development and spread of resistant parasites. The aim of this research was to study the pharmacokinetics and pharmacodynamics of the most commonly used drugs for the treatment of uncomplicated Plasmodium falciparum malaria during the second and third trimester of pregnancy using a pharmacometric approach. This thesis presents a number of important findings that increase the current knowledge of antimalarial drug pharmacology and that may have an impact in terms of drug efficacy and resistance. (1) Lower lumefantrine plasma concentrations at day 7 were evident in pregnant women compared to that in non-pregnant patients. Subsequent in-silico simulations with the final pharmacokinetic-pharmacodynamic lumefantrine/desbutyl-lumefantrine model showed a decreased treatment failure rate after a proposed extended artemether-lumefantrine treatment. (2) Dihydroartemisinin exposure (after intravenous and oral administration of artesunate) was lower during pregnancy compared to that in women 3 months post-partum (same women without malaria). Consecutive in-silico simulations with the final model showed that the underexposure of dihydroartemisinin during pregnancy could be compensated by a 25% dose increase. (3) Artemether/dihydroartemisinin exposure in pregnant women was also lower compared to literature values in non-pregnant patients. This further supports the urgent need for a study in pregnant women with a non-pregnant control group. (4) Quinine pharmacokinetics was not affected by pregnancy trimester within the study population and a study with a non-pregnant control group is needed to evaluate the absolute effects of pregnancy. (5) Finally, a data-dependent power calculation methodology using the log likelihood ratio test was successfully used for sample size calculations of mixed pharmacokinetic study designs (i.e. sparsely and densely sampled patients). Such sample size calculations can contribute to a better design of future pharmacokinetic studies. In conclusion, this thesis showed lower exposures for drugs used to treat uncomplicated Plasmodium falciparum malaria during the second and third trimester of pregnancy. More pharmacokinetic studies in pregnant women with a non-pregnant control group are urgently needed to confirm the current findings and to enable an evidence-based dose optimisation. The data-dependent power calculation methodology using the log likelihood ratio test can contribute to an effective design of these future pharmacokinetic studies.

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.

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.

Une des stratégies pour limiter les neutropénies induites par la chimiothérapie est l’utilisation de granulocyte-colony stimulating factor (G-CSF). Nous avons développé, par une approche de population, un nouveau modèle pharmacocinétique/pharmacodynamique capable de décrire la cinétique des neutrophiles des patients traités au carboplatine, qu’ils aient ou non reçu du G-CSF. Les simulations réalisées à partir de ce modèle ont montré que le G-CSF n’était pas bénéfique chez tous les patients et que la formulation à action longue semblerait plus efficace que les autres formulations. Nous avons également établi des règles de décision permettant d’une part de prédire le risque de neutropénie sévère, et d’autre part d’identifier précocement les patients pour lesquels le G-CSF peut avoir un effet bénéfique. / Granulocyte colony-stimulating factor (G-CSF) is often used in cancer patients receiving cytotoxic drugs to prevent or reduce high grade neutropenia. We developed a new population pharmacokinetic/pharmacodynamic model to describe neutrophil time-course in carboplatin-treated patients, whether or not they received G-CSF. Model simulations showed that G-CSF was not as beneficial as expected in some patients and that the onceper- cycle formulation was more efficient than other formulations. Model-based decision rules were also built to anticipate prolonged high grade neutropenia and early identify patients for whom G-CSF was beneficial.

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.

The elimination of drugs from the body is in many cases performed by the liver. Much could be gained if an accurate prediction of this process could be made early in the development of new drugs. However, for the elimination to occur, the drug molecule needs first to get inside the liver cell. Disposition is the expression used to encapsulate both elimination and distribution. This thesis presents novel approaches and models based on simple in vitro systems for the investigation of processes involved in the hepatic drug disposition. An approach to the estimation of enzyme kinetics based on substrate depletion data from cell fractions was thoroughly evaluated through experiments and simulations. The results that it provided were confirmed to be accurate and robust. In addition, a new experimental setup suitable for a screening environment, i.e., for a reduced number of samples, was generated through optimal experimental design. The optimization suggested that sampling at late time points over a wide range of concentration was the most advantageous. A model, based on data from primary hepatocytes in suspension, for the investigation of cellular disposition of metabolized drugs was developed. Information on the relative importance of metabolism and membrane protein related distribution was obtained by analysis of changes in the kinetics by specific inhibition of the various processes. The model was evaluated by comparing the results to those obtained from an in vivo study analyzed with an especially constructed mechanistic PBPK model. These investigations showed that the suggested model produced good predictions of the relative importance of metabolism and carrier mediated membrane transport for hepatic disposition. In conclusion, new approaches for the investigation of processes involved in hepatic disposition were developed. These methods were shown to be robust and increased the output of information from already commonly implemented in vitro systems.

The overall aim of this thesis was to develop, deploy and evaluate new IT-based methods for supporting treatment and assessment of treatment of advanced Parkinson’s disease. In this condition a number of different motor and non-motor symptoms occur in episodes of varying frequency, duration and severity. In order to determine outcome of treatment changes, repeated assessments are necessary. Hospitalization for observation is expensive and may not be representative for the situation at home. Paper home diaries have questionable reliability and storage and retrieval of results are problematic. Approaches for monitoring using wearable sensors are unable to address important non-motor symptoms. A test battery system consisting of both self-assessments of symptoms and motor function tests was constructed for a touch screen mobile phone. Tests are performed on several occasions per day during test periods of one week. Data is transmitted over the mobile net to a central server where summaries in different symptom dimensions and an overall test score per patient and test period are calculated. There is a web application that graphically presents the results to treating clinical staff. As part of this work, a novel method for assessment of spiral drawing impairment useful during event-driven sampling was developed. To date, the system has been used by over 100 patients in 10 clinics in Sweden and Italy. Evidence is growing that the test battery is useful, reliable and valid for assessment of symptoms during advanced Parkinson’s disease. Infusion of a levodopa/carbidopa gel into the small intestine has been shown to reduce variation in plasma drug levels and improve clinical response in this patient category. A pharmacokinetic-pharmacodynamic model of this intestinal gel infusion was constructed. Possibly this model can assist the process of individualization of dosage for this treatment through in numero simulations. Results from an exploratory data analysis indicate that severity measures during oral levodopa treatment may be factors to consider when deciding candidates for infusion treatment.

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.