Tutorial 6

8/30 12:15 - 2:45, Hewlett 102

Disease Modeling and its Applications in Model-Based Drug R&D: Example of an Integrated Model of Hypertension, Renal Disease Progression and Therapeutic Modulation of the Renin-Angiotensin-Aldosterone System (RAAS)

Anna Georgieva1, Hector de Leon2, Arthur Lo2, Henning Schmidt1 and Jeff Trimmer2

1.Modeling & Simulation, Novartis Pharmaceuticals, East Hanover, NJ. 2.Entelos Inc., Foster City, CA.

This tutorial is aimed at people who wish to learn more about the use of the systems approach of model-based drug research and development to support decision-making in the pharmaceutical industry.

Mathematical drug-disease models are classically categorized as representations of (i) drug exposure aspects (drug dose, kinetics, distribution, metabolism), (ii) aspects related to drug effects (clinical endpoints, pathophysiology, biology, disease progression), and (iii) interactions between drug exposure and effects. These models are developed from empirical phenomenological representations based on data, or derived as a mechanistic representation of biological and physiological processes.

During the last decade, mechanistic models based on systems approaches and incorporating biological and physiological detail have also found applications in the pharmaceutical industry at many levels, including, (1) the characterization of compound pharmacokinetics pre-clinically and its translation to model-based results clinically, (2) the quantification of compound effects in discovery, and (3) the translation of pharmacology across the preclinical-clinical boundary in many ways and for various questions, including validation of target context, biomarker elucidation and prioritization, efficacy and safety across time and length scales (e.g., from molecular to functional levels), as well as patient selection.

In this tutorial, we will demonstrate some of these general concepts through a detailed introduction of the audience to a mechanistic disease model of renin-angiotensin-aldosterone (RAAS), which captures pathophysiological mechanisms of hypertension using both phenomenological and physiological representations of the disease process. We will discuss some of the key modules (systemic, renal, cardiovascular and nervous systems) of this integrated disease model, including the rationale behind the construction of each module based upon a top-down approach driven by the hypotheses to be tested concerning RAAS-modulating therapies and the availability of data required to recreate the appropriate clinical behaviors. For example, the systemic module captures a systems-level representation of the RAAS pathway and its interactions with sodium and water regulation to achieve long-term BP control. The renal module includes a representation of the kidney as an assembly of single nephrons with links to the effect of the glomerular and tubular RAAS pathways on renal tissue remodeling.

Using Entelos' PhysioLab software, we will demonstrate key features of model building, including the bridging of time and spatial scales in the RAAS systems and the presence of feedbacks associated with the effects of disease. We will discuss the model parameterization using literature data and share model-based simulations of systemic and renal biomarkers in select patient phenotypes. We will also demonstrate the process of model validation against independent data sets and the use of the resulting integrated model in evaluating the efficacy of RAAS modulating drugs on blood pressure control and end-organ protection in both early research programs and planned and ongoing clinical trials.

Registration Registered attendees please register for this Tutorial.