Merging Systems Biology with Pharmacodynamics

Abstract

The emerging discipline of systems pharmacology aims to combine analysis and computational modeling of cellular regulatory networks with quantitative pharmacology approaches to drive the drug discovery processes, predict rare adverse events, and catalyze the practice of personalized precision medicine. Here, we introduce the concept of enhanced pharmacodynamic (ePD) models, which synergistically combine the desirable features of systems biology and current PD models within the framework of ordinary or partial differential equations. ePD models that analyze regulatory networks involved in drug action can account for a drug’s multiple targets and for the effects of genomic, epigenomic, and posttranslational changes on the drug efficacy. This new knowledge can drive drug discovery and shape precision medicine.

QSP Toolbox: Computational Implementation of Integrated Workflow Components for Deploying Multi-Scale Mechanistic Models

“…They have involved an assessment of pathways to include (which may be assisted by data (12,13)), simulation of physiologic phenotypes, modeling of populations, and evaluation of predictions (13). Rather than a workflow, Friedrich proposed a model qualification method intended to guide staged QSP modeling projects (14).…”

Systems biology for organotypic cell cultures

“…The field of organotypic cultures seeks ultimately to support more patient-relevant drug safety and efficacy testing, and human-relevant toxicity screening, mainly by using induced pluripotent stem (iPS) cell techniques to produce patient-and population-specific organs-on-chips (Esch et al, 2015;van organs Dougherty, 2013, 2014). The loss of these mechanical and spatial cues in culture alters the physiology and function of cells (Huh et al, 2012a).…”

“…Bioengineered constructs provide for the first time in vitro data of sufficient biological complexity to be used in predictive systems biology models of human response; thus, we propose that these constructs are integral to the successful development of such models. Duinen et al, 2015). While a multiplicity of organotypic cultures has been shown to better recapitulate tissue features (Mortensen et al, 2016), there remain the key hurdles of validating these constructs for safety and efficacy screening and of their widespread adoption to obtain human-relevant and actionable data.…”

“…The metabolism of a compound within each tissue can be described by enhanced PD (ePD) (Iyengar et al, 2012). In the ePD framework, the drug target network is modeled accounting for enzymatic and metabolic reactions, epigenetic/genetic factors, and/or post-translational modifications.…”

Modèles mathématiques dynamiques pour la médecine personnalisée

“…Cependant, cette chute suffisamment complexifié étant donné la croissance récente de la quantité d'information mesurée. C'est la rencontre entre la biologie des systèmes et la pharmacodynamique [16]. ‡…”