Harnessing Human Microphysiology Systems as Key Experimental Models for Quantitative Systems Pharmacology

Abstract

Two technologies that have emerged in the last decade offer a new paradigm for modern pharmacology, as well as drug discovery and development. Quantitative systems pharmacology (QSP) is a complementary approach to traditional, targetcentric pharmacology and drug discovery and is based on an iterative application of computational and systems biology methods with multiscale experimental methods, both of which include models of ADME-Tox and disease. QSP has emerged as a new approach due to the low efficiency of success in developing therapeutics based on the existing target-centric paradigm. Likewise, human microphysiology systems (MPS) are experimental models complementary to existing animal models and are based on the use of human primary cells, adult stem cells, and/or induced pluripotent stem cells (iPSCs) to mimic human tissues and organ functions/structures involved in disease and ADME-Tox. Human MPS experimental models have been developed to address the relatively low concordance of human disease and ADME-Tox with engineered, experimental animal models of disease. The integration of the QSP paradigm with the use of human MPS has the potential to enhance the process of drug discovery and development.

The Microbiome and the Gut‐Liver‐Brain Axis for Central Nervous System Clinical Pharmacology: Challenges in Specifying and Integrating In Vitro and In Silico Models

“…A systems approach is necessary for understanding and treating CNS diseases, and the merging of pharmacology with systems biology has created the field of quantitative systems pharmacology. 4,5,105 The problems only become harder with the need to incorporate the microbiome. Fritz et al 106 review the current status of in silico models.…”

“…As with many computational models of biological systems, the greater challenge is to obtain the data required first to parameterize and then validate the model as accurately representing clinical physiology. 4 Notably, there is the obvious difficulty in obtaining detailed, quantitative descriptions of microbiota sequestered deep within that patient's GI system that might be addressed using single or coupled organ chips. Hence, our discussion turns to assays and OoCs.…”

“…The Microbiome and the Gut-Liver-Brain Axis for Central Nervous System Clinical Pharmacology: Challenges in Specifying and Integrating In Vitro and In Silico Models Kyle G. Hawkins 1 , Caleb Casolaro 2 , Jacquelyn A. Brown 1,3 , David A. Edwards 4 and John P. Wikswo 1,2,3,5, *…”

“…Organson-chips (OoCs), that is, 2D and 3D human tissue constructs typically grown in perfused, microfluidic devices using primary, tissue-resident adult stem cells, or induced pluripotent stem cells (iPSCs) to create microphysiological systems (MPS), 3,4 are one of the newest tool sets being introduced into clinical pharmacology and toxicology. 5,6 Although they are increasingly recognized as being able to recapitulate enough tissue or organ functions to recapitulate a functional unit and serve as useful in vitro human models for quantitative systems pharmacology, 4 their full potential for studying host-microbiome interactions has yet to be realized. This review first examines microbiota-host interactions, exogenously driven microbiota composition perturbations, and treatment outcomes that depend upon microbiota composition, all from the perspective of clinical pharmacology.…”

Applications of the Microphysiology Systems Database for Experimental ADME-Tox and Disease Models

“…1, 2 A number of recent reviews describe in detail an expanding number of MPS models of human organs being developed. [3][4][5][6][7] The goal of all of the MPS models in development or in use has been to produce biologically relevant experimental models that replicate key aspects of normal or diseased human physiology. When these experimental models closely simulate the clinical physiology, they can provide valuable information for computational modeling allowing for a better understanding of normal physiology, as well as the pathophysiology of the disease.…”