Multiscale Mechanistic Modeling in Pharmaceutical Research and Development

Abstract

Discontinuation of drug development projects due to lack of efficacy or adverse events is one of the main cost drivers in pharmaceutical research and development (R&D). Investments have to be written-off and contribute to the total costs of a successful drug candidate receiving marketing authorization and allowing return on invest. A vital risk for pharmaceutical innovator companies is late stage clinical failure since costs for individual clinical trials may exceed the one billion Euro threshold. To guide investment decisions and to safeguard maximum medical benefit and safety for patients recruited in clinical trials, it is therefore essential to understand the clinical consequences of all information and data generated. The complexity of the physiological and pathophysiological processes and the sheer amount of information available overcharge the mental capacity of any human being and prevent a prediction of the success in clinical development. A rigorous integration of knowledge, assumption, and experimental data into computational models promises a significant improvement of the rationalization of decision making in pharmaceutical industry. We here give an overview of the current status of modeling and simulation in pharmaceutical R&D and outline the perspectives of more recent developments in mechanistic modeling. Specific modeling approaches for different biological scales ranging from intracellular processes to whole organism physiology are introduced and an example for integrative multiscale modeling of therapeutic efficiency in clinical oncology trials is showcased.

A pharma perspective on the systems medicine and pharmacology of inflammation

“…The discovery and development of a new compound is characterised by two major consecutive phases: preclinical and clinical, and there are challenges and opportunities for mathematical http modelling at multiple steps in both phases [4]. The preclinical phase usually starts with the identification of a suitable target, followed by the identification of a lead compound (often using high-throughput assays), i.e.…”

Role of Knowledge Management in Development and Lifecycle Management of Biopharmaceuticals

“…While models and simulations are quite commonly used for the establishment of control strategies in the industry, most of these applications are not disseminated publicly and only a few such examples could be located such as the improvement of manufacturing processes through the modeling of chemical plants (60) and research and development through integrative multi-scale modeling frameworks (27). …”

“…From the viewpoint of KM, process models represent accumulated expert knowledge generated over years, which allows the simulation of system behavior in the face of perturbations (27). Dynamic simulations of process models offer a cost-effective approach for exploring design spaces before significant process development is carried out and can be used from the very earliest development stages through scale-up and optimization of operating conditions (80).…”

“…Graphs, charts and Response Surface Methods are included.Visualizing metabolic networks (20), Response Surface Methodology in biotechnology (21) Statistical analyzers Provide quantitative measure of the inherent variability of a phenomena, assessing the current state of control and enabling process improvement.Chemometrics-based PAT (22), Integrated statistical platforms to laboratory management (23) Intelligent agents Decision support tools that are grounded in the emulation of skills for reasoning and inference. Their system is composed by a knowledge base, an inference engine and an interface for the user.Intelligent process management in continuous pharmaceutical operations (24), intelligent decision support in pharmaceutical development (25) Models and simulation Effective integration of knowledge, information, and assumptions with experimental data in one unified representation, to predict outcomes and express relationships.Modeling in decision making for drug development (26), multiscale pharmaceutical mechanistic modeling (27)Dissemination Network and web technologies Interfaces and platforms that help to interconnect resources inside the boundaries of an organization, exploiting the knowledge within the firm. Externalization can be achieved through the use of web technologies (e.g.…”

Integrating Cellular Metabolism into a Multiscale Whole-Body Model

“…In recent years, modeling approaches have been developed describing biological processes at different levels of physiological organization based on multiple, divergent mathematical formalisms [5], [7], [8], [9]. At the whole-body level, physiologically-based pharmacokinetic (PBPK) modeling quantitatively describes the absorption, distribution, metabolization and excretion (ADME) of endogenous and exogenous compounds within mammalian organisms [10], [11], [12], [13].…”