Pyronaridine/Artesunate (PA) 3:1 fixed dose combination is a novel artemisinin-based combination therapy (ACT) in development for the treatment of acute uncomplicated Plasmodium falciparum or Plasmodium vivax malaria. An understanding of both pharmacokinetics and pharmacodynamics of pyronaridine is of importance in order to achieve optimal therapeutic outcome. In this thesis, population pharmacokinetic models for pyronaridine in healthy subjects, and adult and pediatric malaria patients were developed. Pyronaridine pharmacokinetics in both adult and pediatric populations were best described by a two compartment model with first order absorption and elimination from the central compartment. A presence of malaria infection and body weight were the significant covariates that explained pyronaridine pharmacokinetic variability in the adult population. For the pediatric population, age was the only significant covariate that explained pyronaridine pharmacokinetic variability. Monte Carlo simulations were also performed to address differences in pyronaridine exposures among these populations and to explore the exposures of pyronaridine among recommended dosage regimens for pediatric and adult malaria patients. Healthy adults had a higher exposure to pyronaridine as compared to adult malaria patients. For the pediatric population, younger children had a higher exposure to pyronaridine as compared to older children. The overall range of pyronaridine exposures among dosing groups for adult and pediatric malaria patients were relatively similar. The cut-off values of pyronaridine pharmacokinetic parameters associated with successful treatment outcome were also determined by means of receiver operating characteristic (ROC) curve. These cut-off values can be used to optimize the outcome of malaria treatment. Additionally, Cox proportional hazard model was conducted to determine the relationship between several covariates and time to the occurrence of re-infection or recrudescence. The models showed that as the levels of predicted pyronaridine concentrations on day 7 increased, the risks of acquiring re-infection or recrudescence decreased. Finally, pharmacokinetic drug-drug interaction of pyronaridine and ritonavir was assessed based on the overlap pathway for metabolism of both drugs and the high rates of HIV and malaria co-infection. There was an effect of ritonavir on pyronaridine pharmacokinetics. However, the results were not considered clinically relevant. An increase in ritonavir exposure was observed in the presence of fixed dose PA.

Physiologically-based pharmacokinetic (PBPK) modelling is traditionally employed to predict drug concentration-time profiles in plasma and tissues using information from physiology/biology, in vitro experiments and in silico predictions. Model-based analysis of population pharmacokinetic (PK) data is rarely performed in such a mechanistic framework, as empirical compartmental models are mainly utilised for this purpose. However, the combination of traditional PBPK methodologies with parameter estimation techniques and non-linear mixed effects modelling is an approach with progressively increasing impact due to the significant advantages it offers. Therefore, the general aim of this thesis is to illustrate, explore and thus further facilitate the application of physiologically-based pharmacokinetic models in the context of population data analysis. In order to pursue this aim, this work firstly particularly focuses on the population pharmacokinetics of simvastatin (SV) and its active metabolite, simvastatin acid (SVA). The complex simvastatin pharmacokinetics and their clinical significance, due to the association with simvastatin-induced myopathy, provide an excellent case to illustrate the advantages of a mechanistically sound population model. In the current work, both conventional and physiologically-based population models were developed using clinical PK data for SV and SVA. Specifically, the developed model-based approaches successfully quantified the impact of demographics, genetic polymorphisms and drug-drug interactions (DDIs) on the SV/SVA pharmacokinetics. Therefore, they can be of significant application either in the clinic or during drug development in order to assess myopathy and DDI risk. Secondly, in this work the following advantages offered by integrated population PBPK modelling were clearly illustrated through specific applications: 1) prediction of drug concentrations at the tissue level, 2) ability to extrapolate outside the studied population and/or conditions and 3) ability to guide the design (sample size) of prospective clinical studies. Finally, in the current work, further methodological aspects related to the application of this integrated population PBPK modelling approach were explored. Of specific focus was the parameter estimation process aided by prior distributions and the derivation of the latter from different in vitro/in silico sources. In addition, specific methodology is illustrated in this work that allows the incorporation of stochastic population variability in the structural parameters of such models without neglecting the underlying physiological constraints.

Doctor Pharmaceuticae - DPharm / Introduction: Drug-resistant tuberculosis remains a major world health problem and one of the leading cause of death worldwide. Despite adequate adherence to antituberculosis drugs by patients, the emergence of drug-resistance tuberculosis still occurs. This fact implies other factors leading to the emergence of resistant strains of Mycobacterium tuberculosis. A multidrug treatment regimen, which may consist of five to seven different drugs including terizidone, is used in the treatment of drugresistance tuberculosis. Terizidone is part of the multidrug regimen whose pharmacokinetics is scarce in literature and plasma concentration profile unknown. Two molecules of cycloserine joined by terephtalaldehyde moiety makes up a molecule of terizidone, which is thought to undergo complete metabolism into cycloserine in vivo. Additionally, the current literature report that terizidone and cycloserine can be used interchangeably as they are thought to be equivalent. The aim of this thesis was first to develop and validate bioanalytical methods for determination of terizidone and cycloserine in patients’ plasma samples. Secondly, to model population pharmacokinetics of terizidone and cycloserine. Thirdly, to determine the amount of cycloserine resulting from metabolism of terizidone.

Artemisinin compounds are the most potent anti-malarial drugs available in the market. Today, malaria treatment is largely relies on the artemisinin-based combination therapies. Artesunate (AS) is the most widely used artemisinin derivative. In this thesis, we characterized the population pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA) following oral administration of AS in different populations. In Chapter II, we developed a population pharmacokinetic model of AS and DHA in healthy subjects. These subjects received either single- or multiple-dosing of oral AS, as a monotherapy regimen or in combination with pyronaridine, with or without food. In Chapter III, we developed a population pharmacokinetic model of AS and DHA in adult and pediatric patients with uncomplicated falciparum and vivax malaria who were administered oral pyronaridine/artesunate combination once daily for 3 days. We modeled the AS and DHA data simultaneously using a parent-metabolite model that assumed complete conversion of AS to DHA. Following oral administration, AS is rapidly absorbed with maximum concentrations reached at about 0.5 hours post-dose. AS is rapidly converted to DHA. DHA then undergoes rapid metabolism, with an elimination half-life of about 0.8 hours in malarial patients. Inter-individual variability for almost all pharmacokinetic parameters and residual variability for both compounds were estimated by the models. Substantial variability was seen in the pharmacokinetic parameters between the subjects. In healthy subjects, intake of food with the dose was found to delay the absorption of AS significantly, but not the extent of absorption. Weight was also included in this model as a determinant of DHA clearance. When modeling the data from patients, we included weight as part of the model a prioria priori using an established allometric function. No other covariates examined in the analysis were statistically significant. The performance of final models was evaluated using non-parametric bootstrap technique and visual predictive check. The models were found to adequately described the data at hand, and robust with sufficient predictive power. The results can be used as the base to develop a population pharmacokinetic-pharmacodynamic model and as prior information in guiding the selection of optimal sampling schedule for future pharmacokinetic studies of AS.

In this thesis, the population pharmacokinetics of telapristone and its active metabolite, CDB-4453 was evaluated using nonlinear mixed effects modeling (NONMEM®). A two-compartment (parent) one compartment (metabolite) mixture model with first order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. For the Phase I/II pharmacokinetic analysis (effect of renal and hepatic impairment), telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h-1. Moderate renal impairment resulted in a 74% decrease in Ka. Population estimates for oral clearance (CL/F) for the high and low clearance groups were 11.6 L/h and 3.34 L/h, respectively. Twenty-five percent of the subjects were allocated to the high clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmetest) was 0.20/L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. For the pharmacokinetic analysis evaluating the effect of food; food decreased the Ka of telapristone (Ka for the fed and fasted state was 0.467 and 5.06 h-1, respectively). Population estimates of the high and low CL/F groups were 12.0 L/h and 3.15 L/h, respectively. Thirty-one percent of the subjects were allocated to the high clearance group. V2/F, Q/F and V/4 and Fmetest were 52.8 L, 7.53 L/h, 84.8 L and 0.193/L, respectively. CLM/F was 2.10 L/h. An external validation was performed using the final parameter estimates from the pooled pharmacokinetic analysis (effect of renal and hepatic impairment and the effect of food). From this pharmacokinetic analysis, Ka for the fed and fasted state was 0.299 and 2.35 h-1, respectively. Population estimates for the high and low CL/F groups were 11.6 L/h and 3.22 L/h, respectively. The percentage of subjects allocated to the high clearance group was 29%. V2/F, Q/F, V/4 and Fmetest were 52.8 L, 11.6 L/h and 93.8 L and 0.186/L, respectively. CLM/F was 2.23 L/h. The final model did not meet the requirement for adequate predictability using the external validation dataset. However, the external validation dataset only included samples with limited early time points. Because of the limited sampling times, it is difficult to make a conclusion about the overall adequacy of the model. An external validation dataset with more extensive sampling will be needed in order to better assess the predictability final model. This is the first comprehensive review of the pharmacokinetics of telapristone and CDB-4453.

A novel pyronaridine-artesunate (PA) combination is being developed as a 3:1 fixed ratio oral combination against P. falciparum and P. vivax malaria. Pyronaridine (PYR) has been used on a limited basis as monotherapy to treat malaria in some provinces in China since 1970, and there are minimal published data on pharmacokinetics of PYR in humans. In this thesis, the population pharmacokinetics (PPKs) of PYR is studied in different populations. In Chapter II, we develop a PPKs model in 91 healthy subjects participating in a Phase I study of PA. In addition, data from two Phase II and four Phase III studies of PA are pooled, and PPKs of PYR in 321 adult and 319 pediatric patients are investigated separately in Chapter III and IV, respectively. Chapter V provides comparisons of the results from each population. PYR pharmacokinetics in each population is best described by a two-compartment model with first order absorption and elimination from the central compartment. Although the same structural model is used, pharmacokinetics of PYR differs among the three populations. PYR is absorbed faster and more variably in patients. The weight-normalized total apparent volumes of distribution (V/F) in adult and pediatric patients are approximately 5 and 3 times larger than in healthy subjects. Adult and pediatric patients have a mean weight-normalized oral clearance (CL/F) approximately 2 times higher than healthy subjects but the drug is eliminated more slowly in patient populations due to a much larger V/F. The average elimination half-lives are 8, 11 and 18 days in healthy, pediatric and adult patient populations, respectively. Pharmacokinetic modeling suggests that lean body weight is an important predictor of apparent central volume (V2/F) in adult patients while actual body weight is a significant covariate of V2/F and CL/F in children. The parameters obtained from PPK modeling are plausible and estimated with acceptable precision. The final models are evaluated using a nonparametric bootstrap technique and visual predictive check. The final models are robust and adequately capture the overall pyronaridine pharmacokinetics. Further study in a broader patient population will be necessary to examine other covariates that influence pyronaridine pharmacokinetics.

AR-67 is a lipophilic third generation camptothecin analogue, currently under early stage clinical trials. It acts by targeting Topoisomerase 1 (Top1), a nuclear enzyme essential for DNA replication and transcription and is present in two forms, the pharmacologically active lipophilic lactone and the charged carboxylate. In oncology patients participating in a phase I clinical trial, AR-67 lactone was the predominant species in plasma. Similarly to other camptothecins, the identified dose-limiting toxicities for AR-67 were neutropenia, thrombocytopenia and fatigue. In addition, in vitro metabolism studies indicated AR-67 lactone as a substrate for CYP3A4/5 as well as the UGT1A7 and UGT1A8 enzymes localizing in the liver and the gut. Numerous studies have demonstrated the over-expression of transporters in certain tumor types. Here, the effect of interactions between AR-67 and efflux or uptake transporters on the antitumor efficacy of AR-67 in vitro was studied. We showed that BCRP and MDR1 overexpression confers resistance to AR-67. Moreover, we demonstrated the therapeutic superiority of protracted dosing over more intense dosing regimens of AR-67 using xenografts models. Our studies indicated the schedule-dependent expression of Top1 and the preferential partitioning of AR-67 in the tumor tissue. We reason that these are factors that need to be taken into consideration when designing dosing schedules aiming to maximize efficacy. As most cytotoxic drugs, AR-67 has a narrow therapeutic window. Thus, it is essential to identify the variables influencing exposure to this camptothecin analogue. A thorough compartmental pharmacokinetic analysis was performed on the patient data obtained in a phase 1 clinical trial on AR-67. Moreover, sources of intersubject variability associated with obtaining pharmacokinetic parameter estimates were identified and a population covariate pharmacokinetic model was developed. In conclusion, the drug development of AR-67 is a work in process. Findings presented above provide an insight on the factors contributing to its efficacy and toxicity when given to cancer patients.

<p>Progress in individualized drug treatment is of increasing importance, promising to avoid much human suffering and reducing medical treatment costs for society. The strategy is to maximize the therapeutic effects and minimize the negative side effects of a drug on individual or group basis. To reach the goal, interactions between the human body and different drugs must be further clarified, for instance by using mathematical models. Whether clinical studies or laboratory experiments are used as primary sources of information, greatly</p><p>influences the possibilities of obtaining data. This must be considered both prior and during model development and different strategies must be used. The character of the data may also restrict the level of complexity for the models, thus limiting their usage as tools for individualized treatment.</p><p>In this thesis work two case studies have been made, each with the aim to develop a model for a specific human-drug interaction. The first case study concerns treatment of inflammatory bowel disease with thiopurines, whereas the second is about treatment of ovarian cancer with paclitaxel. Although both case studies make use of similar amounts of experimental data, model development depends considerably on prior knowledge about the systems, the character of the data and the choice of modelling tools. All these factors are presented for</p><p>each of the case studies along with current results. Further, a system for classifying different but related models is also proposed with the intention that an increased understanding will contribute to advancement in individualized drug dosage.</p> / Report code: LiU-Tek-Lic-2007:41.

Des modifications physiologiques importantes interviennent au cours de la grossesse. Ces modifications ont un impact sur la pharmacocinétique et/ou la pharmacodynamique des traitements administrés. Chez la femme infectée par le virus du VIH, un traitement antirétroviral adéquat et efficace est indispensable pour la santé de la mère et pour assurer la prévention de la transmission du virus au nouveau-né. Pour un traitement optimal, en termes d’efficacité et de non-toxicité, la connaissance de l’effet de la grossesse sur les concentrations des antirétroviraux chez la mère ainsi que leur passage transplacentaire est primordiale. Dans cette thèse nous avons utilisé une méthodologie adaptée pour cette population : la modélisation non linéaire à effets mixtes. Des données de suivi thérapeutique pharmacologique, ainsi que les données d’un essai clinique multicentrique (TEmAA) ont été analysées grâce à deux logiciel : NONMEM et Monolix.Dans la première étude présentée, nous nous sommes intéressés à la pharmacocinétique dutenofovir chez la femme enceinte. Nous avons mis en évidence un effet relativement important de la grossesse, en effet une augmentation de 39% de la clairance est observée chezla femme enceinte et la femme parturiente. Une augmentation de la dose serait donc souhaitable chez ces femmes. Dans la deuxième étude, nous avons mis en évidence une légère augmentation de l’exposition à la lamivudine au cours de la grossesse, ne nécessitant pas d’adaptation de posologie. Dans la troisième étude, les concentrations de névirpaine chez la mère et son nouveau-né ont été analysées et le schéma d’administration a été évalué.Dans la dernière étude, à partir des concentrations de tenofovir et d’emtricitabine dans le lait maternel qui sont ici reportées pour la première fois chez l’homme, nous avons simulé les profils de concentrations obtenus chez le nourrisson. / Important physiological changes occur during pregnancy. These changes may affect the pharmacokinetics and/or pharmacodynamics of the administered medication. In HIV infected women, antiretroviral treatment adequacy and effectiveness is essential for the health of the mother and for the prevention of HIV transmission to the newborn. For optimal treatment interms of efficacy and tolerance, the effect of pregnancy on antiretroviral concentrations in themother and their transplacental passage have to be assessed.In this work we used the appropriate methodology in this population: non linear mixed effects modeling. Data from therapeutic drug monitoring, as well as data from a multicenter clinical trial (TEmAA) were analyzed using: NONMEM or Monolix. In the first study presented, we investigated the pharmacokinetics of tenofovir in pregnant women. We observed a relatively large effect of pregnancy, a 39% increase of the apparent clearance in pregnant and parturient woman. A dose increase should be therefore investigated in these women. In the second study, we demonstrated a slight increase in lamivudine exposure during pregnancy. This increase does not require dose adjustment. In the third study, the concentration of nevirapinein the mother and her newborn were analyzed and the administration scheme was evaluated.In the last study, based on concentrations of tenofovir and emtricitabine in breast milk that arereported here for the first time in humans, we simulated the concentration profiles obtained ininfants.

Les modifications physiopathologiques induites par l’obésité sont susceptibles de modifier la pharmacocinétique d’un grand nombre de médicaments. Toutes les étapes peuvent-être touchées : modification des compartiments de l’organisme, de la fonction rénale et de l’expression des protéines du métabolisme. L’intensité des variations induites reste difficile à anticiper en l’absence d’études spécifiques, ce qui pose également la question du choix du meilleur estimateur de poids dans l’expression du schéma posologique du médicament chez le sujet obèse. Nous avons évalué l’impact de différents descripteurs de poids sur les variabilités inter-individuelles de trois médicaments couramment utilisés en diabétologie, dans la douleur et en cancérologie. Une modélisation a été faite en pharmacocinétique de population (Monolix®) avec une évaluation des descripteurs de poids (poids de masse maigre, poids idéal, poids total, surface corporelle…). Pour la metformine (n=105 patients), molécule fortement hydrophile, CL/F et V/F augmentent avec le poids. Le poids de masse maigre est le meilleur descripteur de poids pour les deux paramètres et permet d’abaisser de manière importante la variabilité inter-individuelle. Dans le cas de la morphine (n=31), aucun descripteur n’est corrélé à CL/F ou V/F dans une population de sujets atteints d’obésité morbide. L’analyse de l’imatinib (n=54), de lipophilie plus importante, et de son métabolite actif montre que le poids idéal est la covariable la plus performante. Son impact n’explique cependant qu’une part minime de la variabilité de CL/F et ne remet pas en cause le principe d’une dose fixe. Les résultats confirment l’intérêt des méthodes de pharmacocinétique de population dans l’évaluation des covariables morphologiques, et indiquent qu’il n’existe pas de descripteur de poids universel. Ces résultats doivent nous encourager à évaluer systématiquement l’impact de l’obésité avec des modèles de population. Dans certains cas, des études de confirmation comparant différents schémas devraient-être mises en place. / Pharmacokinetic of drugs may be altered by pathophysiological changes associated with obesity: renal function, body compartments, expression of metabolism proteins. Real impact may be difficult to appreciate due to small number of specific studies. What is the best size-descriptor for optimal dosing in obesity remains a question of importance. Impact of different size descriptors was studied for three drugs currently used in diabetology, pain and oncology. Population pharmacokinetic modeling was done using Monolix® software to evaluate different covariates (LBW, TBW, BSA, …). CL/F and Vd/F of metformin, highly hydrophilic drug, increases positively with body weight (n=105). LBW was the best size-descriptor leading to substancial decrease in the between-subject variability BSV. No size-descriptors showed significant impact for morphine (n=31). Ideal body weight is the best size-descriptor for imatinib and its main metabolite (n=54), lipophilic drug. It explains only a small part of BSV and fixed dosing stays justified. Population PK analysis are the most formal assessment of morphological covariates and no single size descriptor can described all variabilities. Results must lead us to more systematic population PK analysis. Confirmation studies comparing different dosing regimens have to be done.