Mechanism-based pharmacokinetic/pharmacodynamic PK/PD modeling of corticosteroids and antiretrovirals

Mechanism-based pharmacokinetics (PK) and pharmacodynamics (PD) models represent a powerful tool to understand the pathogenesis of disease and examine the effects of drug treatment in various diseases. This thesis aims to develop mechanistic PK/PD models of selected drugs: pramlintide in patients with Type 1 diabetes mellitus (T1DM), methylprednisolone (MPL) in rats and various antiretroviral agents in HIV-infected patients.;Normal blood glucose concentrations are tightly regulated by a complex interplay of multipal factors. Patients with T1DM often manifest both insulin and amylin deficiency, with the latter playing an important role in postprandial glycemic control. Insulin resistance and impaired beta-cell function underlie the pathogenesis of Type 2 diabetes mellitus (T2DM). Corticosteroid (CS) has been well known for their undesirable side effects of inducing insulin resistance and T2DM. This thesis investigated the effects of pramlintide on postprandial glycemic control in patients with T1DM and MPL on glucose regulation in rats. Sequential PK/PD data analysis was performed to quantify and describe drug effects. A mechanism-based PK/PD model was developed based on major pharmacological actions of pramlintide: delayed gastric emptying and suppression of postprandial glucose production. An extended dual indirect response model appropriately captured the effects of pramlintide on postprandial glucose turnover. The acute and chronic effects of MPL on plasma glucose, insulin and free fatty acids (FFA) were assessed in rats. The MPL dosing caused dramatic changes in plasma insulin and FFA concentrations. The basic glucose-insulin feedback model was selected and extended by including the component of FFA with multiple physiological interactions with glucose and insulin. Food intake influences were incorporated into the model to characterize the effects of exogenous nutrient supply. Further, the glucocorticoid receptor-mediated effects of MPL on glucose regulation were studied after integrating previously reported data under different study designs. Various PD markers in three target tissues including liver, skeletal muscle and white adipose tissue were tested and included in this meta-model. The nuclear drug-receptor complex served as the driving force for regulation of downstream target gene expression in relation to glycemic control within different tissues. This meta-model advances our knowledge and provides quantitative hypothesis for the receptor/gene/protein mediated MPL effects on glucose regulation in each important tissue.;The HIV monotherapy trials provide the best opportunity to learn about the pharmacodynamic effects of antiretroviral (ARV) new molecular entities (NMEs) under development. Knowledge of dose-response information is critical to rationally select doses for monotherapy trials, reduce risk of later-stage trial failures, and better inform the go-no go decision. This thesis adapted a mechanistic HIV disease model with modifications. This model was used as a framework to derive the scaling factor (SF), which represents the in vitro to in vivo correlation for each representative lead case study. We further qualified the proposed model-based framework for existing drugs to demonstrate the application of the framework for other ARVs. The results indicated that for most antiviral drugs, in vitro drug potency (EC50) and in vivo model-based efficacious concentration (IC50 ) can be linked through a class-specific SF. The derivedSF for ARV drugs within a given class permits a way to efficiently propagate knowledge from one compound to others and facilitates dose selection for monotherapy trials of NME.;In summary, this thesis extends the mechanistic understandings of pramlintide and CS effects on glucose regulation and exemplifies that mechanism-based PK-PD-disease model represents a useful tool to assist dose selection for ARV monotherapy trials.