Most patients with bladder cancer are in the stage of non-muscle-invasive bladder cancer (NMIBC), while 30% of patients progress to the life-threatening muscle-invasive bladder cancer (MIBC) stage because of distant metastases. The selection of treatment options depends on the bladder cancer stage. We established a relationship network for the proteins from the mice urine samples collected during the progression of bladder cancer based on biological pathways and developed population pharmacodynamic models for the proteins in the light of their relationship network. Models that can quantitatively describe changes in the protein profiles of IL1a, IL1b, Csf2, and Casp3 in mice urine samples over time during bladder cancer progression were developed with the consideration of gender differences and progressing age. Our results assist the identification of the early protein diagnostic biomarkers in urine for detecting bladder cancer at its early stages and apply appropriate treatments on patients.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Michael D. Apley / The discovery of modern antimicrobials in the early 20th century revolutionized treatment of infectious diseases. Less than 100 years later, antimicrobial resistance has become a global threat to public health. With the rise of antimicrobial resistance, the question that remains to be answered is: Can dosing regimens provide maximal clinical efficacy, yet minimize the development of antimicrobial resistance? A pharmacokinetic / pharmacodynamic approach was utilized to investigate oxytetracycline regimens that would impart efficacy while minimizing the potential for resistance development due to plasmid transfer. An in vitro pharmacodynamic model was used to quantify the response of a Pasteurella multocida isolate to two oxytetracycline dosing regimens. The PK/PD index most closely related to efficacy was the Cmax:MIC. The in vitro pharmacodynamic model was then used to investigate the effects of antimicrobial exposure on plasmid transfer. A mixed population of oxytetracycline-susceptible and resistant bacteria was exposed to two dosing regimens and plasmid transfer was quantified. When oxytetracycline concentrations exceeded the MIC of the recipient, development of resistance was suppressed. The same donor and recipient bacteria were used in an in situ swine model to validate the in vitro findings. Following surgical implantation of porous membrane straws containing the mixed bacterial population, animal subjects in the treatment groups received one of two oxytetracycline treatments. Oxytetracycline concentrations in the plasma and interstitial fluid were quantified. Plasmid transfer within the implant membranes was quantified and correlated to pharmacokinetic measures in the animal. Plasmid transfer rates in the implant membranes did not correlate to the investigated pharmacokinetic parameters. The study methodologies in this dissertation should serve as a foundation for future studies in antimicrobial pharmacokinetic/pharmacodynamic research. The results presented here show that the bacterial response to oxytetracycline can be optimized in a concentration dependent manner and that antimicrobial resistance development through plasmid transfer can be suppressed in vitro when oxytetracycline concentrations exceed the MIC of the recipient bacteria. These results suggest that a proper balance between clinical efficacy and minimizing antimicrobial resistance can be achieved for oxytetracycline through appropriate dosing regimens and drug formulations.

The aim of this work is to evaluate the fuzzy system for different types of patients for levodopa infusion in Parkinson Disease based on simulation experiments using the pharmacokinetic-pharmacodynamic model. Fuzzy system is to control patient’s condition by adjusting the value of flow rate, and it must be effective on three types of patients, there are three different types of patients, including sensitive, typical and tolerant patient; the sensitive patients are very sensitive to drug dosage, but the tolerant patients are resistant to drug dose, so it is important for controller to deal with dose increment and decrement to adapt different types of patients, such as sensitive and tolerant patients. Using the fuzzy system, three different types of patients can get useful control for simulating medication treatment, and controller will get good effect for patients, when the initial flow rate of infusion is in the small range of the approximate optimal value for the current patient’ type.

Le traitement par éfavirenz, un médicament antirétroviral, a été associé avec des changements de profil lipidique potentiellement défavorables. Ce travail a abordé la question de savoir si ces effets dépendent des concentrations plasmatiques d’éfavirenz et, dans ce cas, si sa posologie pourrait être optimisée sans perte d'efficacité.Un modèle de pharmacocinétique de population a été développé à partir de données d’enfants infectés par le VIH. La simulation d’une population normalisée sous éfavirenz aux posologies recommandées montre que 15 % des enfants auraient des concentrations insuffisantes 12 heures après la prise, ce qui serait associé à un risque de la réplication virale de 23 %.Pour décrire la relation entre taux plasmatiques d'éfavirenz et changements de taux de cholestérol, des modèles de pharmacocinétique-pharmacodynamique (PK-PD) de réponse indirecte ont été développés. Le modèle sélectionné prédit que les taux d’éfavirenz individuels sont associés à une augmentation des lipoprotéines de haute densité sur 5 ans, et des lipoprotéines de basse densité durant 4 mois avec un retour progressif aux valeurs de base.Pour évaluer l’impact des concentrations d'éfavirenz sur l'efficacité, un modèle dynamique PK-PD a décrit la relation entre ces concentrations et l’évolution de la charge virale VIH et du taux de CD4. Un score d’efficacité a été développé sur la base d’hypothèses pharmacodynamiques pour prédire le risque de la réplication virale.L’utilisation de l’éfavirenz aux posologiques recommandées par la Food and Drug Administration aux Etats-Unis semble assurer une efficacité optimale et des changements potentiellement favorables dans les fractions de cholestérol. / As other antiretroviral drugs, treatment with efavirenz has been associated with potentially unfavorable lipid profile changes in adults and in children. The thesis addressed the question of whether these changes depend on efavirenz plasma concentrations and if dose adjustments could be envisioned without loss of efficacy.To estimate individual efavirenz exposure over 24 hours, a population pharmacokinetic model was developed using data from HIV infected children. Simulations for a normalized population receiving efavirenz dosed according recommendations predicted that 15% of children would have insufficient mid dose concentrations, associated with a 23% risk of viral replication.To describe the relationship between efavirenz concentrations and cholesterol changes, population pharmacokinetic-pharmacodynamic (PK-PD) indirect response models were developed. The selected model predicted that individual efavirenz concentrations were associated with an increase in high-density lipoprotein concentrations over 5 years but with an increase in low-density lipoprotein concentrations only during the first 4 months of treatment followed by a gradual return to baseline.To study the importance of efavirenz concentrations with regard to efficacy, a PK-PD dynamics model was developed to describe the relationship between concentrations and HIV RNA load and CD4 cell count evolutions. A score was defined based on a pharmacodynamic hypothesis to predict the risk of viral replication.Using US Food and Drug Administration dosing recommendations in children ensure optimal efficacy and potentially favorable changes in cholesterol fractions.