Quantitative Systems Pharmacology Approaches Applied to Microphysiological Systems (MPS): Data Interpretation and Multi-MPS Integration

Our goal in developing Microphysiological Systems (MPS) technology is to provide an improved approach for more predictive preclinical drug discovery via a highly integrated experimental/computational paradigm. Success will require quantitative characterization of MPSs and mechanistic analysis of experimental findings sufficient to translate resulting insights from in vitro to in vivo. We describe herein a systems pharmacology approach to MPS development and utilization that incorporates more mechanistic detail than traditional pharmacokinetic/pharmacodynamic (PK/PD) models. A series of studies illustrates diverse facets of our approach. First, we demonstrate two case studies: a PK data analysis and an inflammation response––focused on a single MPS, the liver/immune MPS. Building on the single MPS modeling, a theoretical investigation of a four‐MPS interactome then provides a quantitative way to consider several pharmacological concepts such as absorption, distribution, metabolism, and excretion in the design of multi‐MPS interactome operation and experiments.

[1]  R. Gamelli,et al.  Genomic responses in mouse models poorly mimic human inflammatory diseases , 2013, Proceedings of the National Academy of Sciences.

[2]  J L Coolens,et al.  Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. , 1987, Journal of steroid biochemistry.

[3]  S. Renard.  A decade of change. , 2013, Radiology management.

[4]  G. Su,et al.  Kupffer cell activation by lipopolysaccharide in rats: Role for lipopolysaccharide binding protein and toll‐like receptor 4 , 2000, Hepatology.

[5]  Michael L Shuler,et al.  A novel system for evaluation of drug mixtures for potential efficacy in treating multidrug resistant cancers , 2009, Biotechnology and bioengineering.

[6]  L. Griffith,et al.  Bioreactor technologies to support liver function in vitro. , 2014, Advanced drug delivery reviews.

[7]  J. Arrowsmith,et al.  Trial Watch: Phase II and Phase III attrition rates 2011–2012 , 2013, Nature Reviews Drug Discovery.

[8]  T. Hartung.  Toxicology for the twenty-first century , 2009, Nature.

[9]  Alan Wells,et al.  A microphysiological system model of therapy for liver micrometastases , 2014, Experimental biology and medicine.

[10]  Yordan Kostov,et al.  The Design and Fabrication of Three‐Chamber Microscale Cell Culture Analog Devices with Integrated Dissolved Oxygen Sensors , 2008, Biotechnology progress.

[11]  Nancy L Allbritton,et al.  In vitro generation of colonic epithelium from primary cells guided by microstructures. , 2014, Lab on a chip.

[12]  L M Sweeney,et al.  A cell culture analogue of rodent physiology: Application to naphthalene toxicology. , 1995, Toxicology in vitro : an international journal published in association with BIBRA.

[13]  Michael L Shuler,et al.  Pumpless microfluidic platform for drug testing on human skin equivalents. , 2015, Lab on a chip.

[14]  J. Cidlowski,et al.  Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. , 2005, The New England journal of medicine.

[15]  Matthew H. M. Lim,et al.  Perfused multiwell plate for 3D liver tissue engineering. , 2010, Lab on a chip.

[16]  Jong Hwan Sung,et al.  A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip. , 2010, Lab on a chip.

[17]  S. Bolz,et al.  A microfluidic platform for probing small artery structure and function. , 2010, Lab on a chip.

[18]  D. Kirschner,et al.  A methodology for performing global uncertainty and sensitivity analysis in systems biology. , 2008, Journal of theoretical biology.

[19]  K. Helle,et al.  History and Perspectives , 2017 .

[20]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[21]  Kristin M. Fabre,et al.  Organs-on-chips (microphysiological systems): tools to expedite efficacy and toxicity testing in human tissue , 2014, Experimental biology and medicine.

[22]  M. Delp,et al.  Physiological Parameter Values for Physiologically Based Pharmacokinetic Models , 1997, Toxicology and industrial health.

[23]  Hartmut Derendorf,et al.  Modeling of Pharmacokinetic/Pharmacodynamic (PK/PD) Relationships: Concepts and Perspectives , 1999, Pharmaceutical Research.

[24]  A. Sandberg,et al.  Inactivity in vivo of Transcortin-Bound Cortisol , 1962, Science.

[25]  T. Miyakawa,et al.  Genomic responses in mouse models poorly mimic human inflammatory diseases , 2013 .

[26]  Young Sang Kim,et al.  Kinetics of binding of LPS to recombinant CD14, TLR4, and MD-2 proteins. , 2007, Molecules and cells.

[27]  D. Lauffenburger,et al.  Receptors: Models for Binding, Trafficking, and Signaling , 1993 .

[28]  Jiajie Yu,et al.  In vitro 3D human small intestinal villous model for drug permeability determination. , 2012, Biotechnology and bioengineering.

[29]  M L Shuler,et al.  Combining Cell Culture Analogue Reactor Designs and PBPK Models to Probe Mechanisms of Naphthalene Toxicity , 2000, Biotechnology progress.

[30]  P. Siiteri,et al.  Rates of dissociation of steroid and thyroid hormones from human serum albumin , 1990, The Journal of Steroid Biochemistry and Molecular Biology.

[31]  Patrick Poulin,et al.  Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution. , 2002, Journal of pharmaceutical sciences.

[32]  L. Griffith,et al.  Tissue Engineering--Current Challenges and Expanding Opportunities , 2002, Science.

[33]  D. Torpy,et al.  Validation of a simple method of estimating plasma free cortisol: role of cortisol binding to albumin. , 2009, Clinical biochemistry.

[34]  Michael Hay,et al.  Clinical development success rates for investigational drugs , 2014, Nature Biotechnology.

[35]  L. Griffith,et al.  Capturing complex 3D tissue physiology in vitro , 2006, Nature Reviews Molecular Cell Biology.

[36]  Shuichi Takayama,et al.  Microfeature guided skeletal muscle tissue engineering for highly organized 3-dimensional free-standing constructs. , 2009, Biomaterials.

[37]  Davide Verotta,et al.  Pharmacokinetic–Pharmacodynamic Modelling: History and Perspectives , 2006, Journal of Pharmacokinetics and Pharmacodynamics.

[38]  M. Alvinerie,et al.  Interspecies variations of corticosteroid-binding globulin parameters. , 1996, Domestic animal endocrinology.

[39]  S. Klieber,et al.  Morphological behaviour and metabolic capacity of cryopreserved human primary hepatocytes cultivated in a perfused multiwell device , 2015, Xenobiotica; the fate of foreign compounds in biological systems.

[40]  Wan-Wan Lin,et al.  A cytokine-mediated link between innate immunity, inflammation, and cancer. , 2007, The Journal of clinical investigation.

[41]  G. Su,et al.  Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[42]  Ravi Iyengar,et al.  Quantitative and Systems Pharmacology in the Post-genomic Era : New Approaches to Discovering Drugs and Understanding Therapeutic , 2011 .

[43]  Michael L. Shuler,et al.  Animal on a chip: a microscale cell culture analog device for evaluating toxicological and pharmacological profiles , 2001, MOEMS-MEMS.

[44]  W. Yeh,et al.  LPS/TLR4 signal transduction pathway. , 2008, Cytokine.