Pharmacokinetic and Pharmacodynamic Analysis of Incretin Mimetics in Glucose Homeostasis and Treatment of Type 2 Diabetes Mellitus

Hyperglycemia is a hallmark of type 2 diabetes mellitus (T2DM), which results from deficiencies in multiple pathophysiological components that are critical to maintaining glucose homeostasis, such as altered secretion and effects of insulin, defects in pancreatic beta cell function, a reduction in beta cell mass over time, and deficiencies within pancreatic alpha cells. The incretin effect refers to the glucose-dependent amplification of insulin secretion, by hormones secreted from the gastrointestinal track in response to ingestion of nutrients. In humans, two main incretin hormones account for 90% of the incretin effect; glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide - 1 (GLP-1). The GLP-1 receptor is widely expressed, and the mechanisms of action of the incretin hormones includes both pancreatic and extrapancreatic effects.;Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist (39 amino acid peptide) with both immediate- and extended-release (IR and ER) formulations approved for the treatment of T2DM. There are four main mechanisms of action associated with exenatide: glucose-dependent insulin secretion, glucose-dependent suppression of elevated postprandial glucagon secretion, slowing of gastric emptying, and increased satiety. The IR formulation is administered twice daily to provide peak drug concentrations that correspond with times of peak post-prandial glucose concentrations to maximize the glycemic benefits that result from multiple mechanisms of action.;A comprehensive population PK model of the IR formulation of exenatide was developed in Chapter 2 that quantifies the influence of weight and renal function, as well as linear and nonlinear elimination processes, on drug disposition. This comprehensive PK analysis yielded a model that is qualified over a broad range of drug concentrations and patient conditions. This model was also leveraged within subsequent chapters of this dissertation and has utility in future PK modeling of alternative formulations of exenatide. For the PK properties of the ER formulation, due to the preserved peptide structure of the released drug, only the absorption related properties differ from the IR formulation. Thus, the original model from Chapter 2 was expanded to quantify the PK profiles associated with the ER formulation, including a complex absorption system described by three parallel processes (Chapter 3). A simulation study was then performed showing that the sustained exenatide exposure from the ER formulation, achieved through slow drug release from microspheres (weeks) relative to the fast elimination rate (hours), should result in no clinically meaningful differences in times to reach steady- state or to decrease to undetectable values in patients with decreasing renal function (Chapter 4).;Thorough QT/QTc studies have become an integral part of early drug development programs, with major clinical and regulatory implications. We expand upon existing PD models of QT interval analysis by incorporating the influence of glycemic changes on the QT interval in a semi-mechanistic manner; quantifying the influence of glucose on HR and QT intervals following a single meal and across a 24-hour period (Chapter 5). This analysis revealed a peak change in the QT interval that occurs with a time lag of 2-3 hours after a meal. The expansion of the baseline QT model (Chapter 5) to include the PK and glucose-lowering effects of exenatide demonstrated that for therapeutic agents that alter post-prandial glucose (PPG) homeostasis, the QT interval cannot be directly compared to placebo without first accounting for confounding factors, either through PK/PD modeling or careful consideration of mealtime placement in the study design (Chapter 6).;In Chapter 7, a consolidated mechanism-based PK/PD model was developed that focuses on the complex interplay among the critical components involved in glucose regulation during postprandial and fasting conditions, which includes glucose, insulin, glucagon, incretin hormones, and gastric emptying rates. These system components were effectively coupled with mechanisms of action of GLP-1 receptor agonists within a single semi-mechanistic model of the IR formulation of exenatide in subjects with T2DM. Simulations suggest that the slowing of gastric emptying is the predominant mechanism for the suppression of post-prandial glucose (PPG) concentrations, and that under fasting conditions, the stimulation of insulin release is the primary mechanism contributing to the glucose-lowering effects of exenatide.;Subsequently, the short-term PK/PD model of exenatide (Chapter 7) was successfully extended to predict FPG and HbA1c profiles following long-term (i.e., 30 weeks) therapy (Chapter 8).;In summary, this dissertation provides a quantitative framework for evaluating the mechanisms underlying glucose homeostasis, the role of glycemic influences on the QT interval, and concentration-effect relationships within these systems for exenatide in T2DM. This work expands the knowledge base for incretin mimetics by providing a comprehensive evaluation of the PK/PD of exenatide (a model GLP-1 agonist) and models that can be leveraged in the development and clinical utilization of long- and short-acting therapeutic strategies based on incretin signaling pathways. (Abstract shortened by UMI.).