Pharmacokinetic / pharmacodynamic / disease progression model of drug effects in a rat model of rheumatoid arthritis.

摘要

Mechanism-based modeling is a useful tool for characterization of physiological systems and pathological pathways in diseases. Development of mechanism-based pharmacokinetic (PK) / pharmacodynamic (PD) model allows quantitative assessment of how drug effects on the various components along its pharmacological pathway and helps better understanding of the factors that affect drug safety and efficacy. The overall aim of this project is to apply the mechanism-based modeling approach to investigate the pathology of rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease, as well as the PK / PD properties of several RA therapeutic agents.;Chapter 1 provides some general background information regarding the use of PK / PD modeling in inflammation. This chapter introduces many types of biomarkers used for assessing inflammation pathology as well as various modeling approaches that have been used for studying the pathways involved in different inflammatory diseases.;Chapters 2 to 5 present the studies we have performed to investigate the drug effects in RA. Collagen-induced arthritic (CIA) rat model was the animal model used in all our studies. Paw swelling was monitored throughout the studies as an indicator of disease activity, and drug was administered to the rats on the peak of disease activity, which was on day 21 post-induction. After drug injection, blood samples were collected for assessing drug concentrations at different time points.;Chapter 2 illustrates a study that investigated the PK / PD of etanercept, a TNF-alpha inhibitor, as well as the natural disease progression in the CIA rat model.;Chapter 3 describes a similar study where the PK / PD relationship of anakinra was investigated. Anakinra is a selective antagonist to IL-1 receptor and can block the activity of IL-1alpha and IL-1beta. A transduction-based feedback model incorporating logistic growth rate was used to capture disease progression, and anakinra was supposed to elicit its effects via blockade of the paw edema production process (kin). Maximum inhibition by anakinra on paw edema (Imax) was estimated to be 0.279.;Chapter 4 focuses on the effects of our third therapeutic biologic of interest, abatacept, which is a blocker for the co-stimulation signal required for T cell activation.;Chapter 5 presents a mechanistic disease progression model describing the interplay between the pro-inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) and bone remodeling biomarkers, as well as their roles in regulating bone mineral density (BMD) in CIA rats. This model was developed based on the data obtained during natural disease progression and DEX therapy.;Overall, our results indicated that all three tested biologics, etanercept, anakinra, and abatacept, have modest effects on suppressing the paw edema symptom in CIA rats. Comparison of the drug efficacy parameters revealed that etanercept, as a TNF-alpha inhibitor, has the most inhibitory effects on the production of paw edema among the three agents. On the other hand, DEX, as a small-molecule drug, is effective in reducing paw swelling, and this is likely because of its efficacy for inhibiting the expressions of the major inflammatory cytokines. The mechanistic model built in the DEX study provides a framework that collectively describes the progression of inflammatory cytokines, bone-related biomarkers, and disease endpoints under arthritic and DEX-treated conditions, and it can also predict their time-concentration profiles under the intervention of different therapeutic approaches. (Abstract shortened by UMI.).