Introduction to a manuscript series on the characterization and use of microphysiological systems (MPS) in pharmaceutical safety and ADME applications

Abstract

Opportunities in the drug discovery/development process for potential MPS incorporation.

Current and potential future applications of human stem cell models in drug development

“…Primary cultures from up to 11 human organs were generated, grown in bioengineered platforms, and scaled to represent the fraction of blood flow that each organ receives in humans so that drug metabolites from each organ could be evaluated for toxicity in downstream organs, as would occur in vivo (6). In parallel with these experimental studies, a working group of scientists from pharmaceutical companies (the Innovation and Quality Consortium's Microphysiological Systems working group) was invited to opine on the need for the new models and technology from a pharma perspective (3,7).…”

“…What criteria will the FDA define as necessary and sufficient for use of stem cells in the drug approval process? Although the FDA has established internal programs for studying stem cell models, indicating its belief in the potential importance of these models, data using any human stem cell models have yet to be submitted to the FDA for consideration as part of a drug application (3,14). In the meantime, stem cell culture models continue to increase in complexity and more closely approximate the organs they represent, disease models using human stem cells have been shown to duplicate clinical aspects of the diseases and provide new insights concerning pathophysiology, new potential drug targets continue to be identified, and human stem cell-based biobanks are growing, allowing consideration of biodiversity.…”

“…Given the progress in physiologic, pathophysiologic, and pharmacologic studies using human stem cell-derived systems, many pharmaceutical companies have now established internal programs or are collaborating with academic or commercial groups that are studying these model systems (3,7,14). Though the details of these programs have not been publicly disclosed, based on preliminary publications and privileged discussions (3,7,14), it appears that human cell-based in vitro systems are being used for early toxicity testing of promising drugs, pharmacokinetic analyses, and modeling of pathways that are dysregulated in complex human disorders, such as inflammatory bowel disease and host-pathogen interactions. It is envisioned that these model systems could also be used for target identification, high-throughput screening, lead optimization and selection, and preclinical pharmacokinetic and pharmacodynamic testing.…”

“…Current and potential future applications of human stem cell models in drug development Mark Donowitz, 1,2 Jerrold R. Turner, 3 Alan S. Verkman, 4 and Nicholas Constantine Zachos 1 1 Division of Gastroenterology, Department of Medicine, and 2 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 3 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 4 Departments of Medicine and Physiology, UCSF, San Francisco, California, USA.…”

“…However, the value of using human models for drug development has only relatively recently been appreciated. An FDA review of drug development reported that 80% to 90% of drug candidates entering phase I clinical trials fail, with the most common causes of failure being lack of efficacy and toxicity (1)(2)(3). Lack of efficacy accounted for 57% of failures.…”