Pharmacokinetics and pharmacodynamics of selected compounds affecting bone homeostasis
Abraham, Anson Kunjachan
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A major goal of this thesis is to characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of selected agents that have the potential to alleviate conditions of excessive bone resorption. A model-based approach was used for developing a new class of compounds intended for use in osteoporosis and for hypothesis testing of the target-mediated properties of interferon (IFN)-β. Calcium-sensing Receptor (CaR) Antagonists. The CaR antagonists are a new class of orally active compounds currently in development for the treatment of osteoporosis. If approved, these agents would represent novel anabolic drugs and a potential alternative to recombinant parathyroid hormone (PTH) for severe cases of osteoporosis. To aid development of these compounds, a PK/PD model was developed that characterized the PTH-ionized calcium (Ca +2 ) regulatory pathway (Ch. 1). This model was then adapted to include compound specific parameters and CaR binding properties to predict the PTH response for a series of CaR antagonists (Ch. 2 and 3). Interferon-β. IFN-β, a compound known for its anti-inflammatory and anti-proliferative effects has been implicated in the regulation of osteoclast activity. The PK of IFN-β has been hypothesized to exhibit non-linear target-mediated drug disposition (TMDD). To test this hypothesis, the PK/PD of murine IFN-β was studied in wild-type and IFNAR-1 receptor subunit knockout mice, and the differential exposure-response profiles were well characterized using a TMDD systems model (Ch. 5). The role of IFN-β in inhibiting osteoclast activity in distal femur bones was also studied in a disease progression model of multiple myeloma (Ch. 6). Analysis of Target-mediated Drug Disposition Models. The general TMDD model, as well as its rapid-binding approximation, has shown considerable utility for understanding the disposition and dynamics of drugs that exhibit this phenomenon. A local sensitivity analysis of the rapid binding TMDD model was conducted to assess sensitivity of the model output to parameter perturbations (Ch. 7). In addition, the pharmacodynamic consequences of incorporating specific tissue distribution and receptor dimerization were evaluated using a family of TMDD models (Ch. 8). These studies provide insights into TMDD systems and may be used to guide the design and analysis of studies seeking to delineate the PK/PD properties of drugs for which TMDD behavior is relevant.