Boston QSP May Event "QSP in Drug Discovery": The Blog
Tissue Chip Technology: Taking Human Physiology in vitro
Author: Sarah Yunes
Editors: Jae Yang and Rajiv P. Shrestha
One of the primary challenges in successfully making new drugs is getting potential therapeutics from in vitro assays and animal models to successfully being approved as a drug in clinical trials. Frequently, drug candidates will be effective in animal studies, but clinical trials show them to be ineffective or toxic, due to physiological differences between humans and animals. This is a costly setback, as it wastes time and resources on drug candidates that will not make it to market. There is a desperate need for models that better represent human physiology to determine if a possible drug will be effective and safe in humans. This has led to the development of microphysiological systems (MPS), also called tissue chips (TC) or organs on chips (OOC), which can serve as in vitro analogs of human organs and systems in drug development. To further discuss tissue chip technology, the speaker for our May event was Dr. Murat Cirit, the principal investigator of the Translational Center of Tissue Chip Technologies (TC2T) at MIT and founder of Javelin Biotech, a company focused on assisting pharmaceutical clients in using tissue chip technologies to improve the drug development and clinical trial process. His talk was titled Merging Human-relevant in-vitro Models with Quantitative Systems Pharmacology.
Dr. Murat Cirit during his talk
The goal of MPS is to create functional units of organs that can be used to check clinical parameters relevant to the organ’s response to drugs. This method allows traditionally difficult-to-make biological observations to get a better understanding of how drugs affect the human body, using a long-lasting tissue culture system to be combined with quantitative systems pharmacology (QSP) modeling. The system can be used to test a variety of drug modalities. It is also easier and more cost-effective to scale this technology for testing multiple drugs. Additionally, the ability to test on a variety of human samples can help pave the way for personalized medicine. Tissue chips that model multiple organs can even be combined to simulate multiple systems. All of this makes tissue chip technologies the best in vitro representation of human biology thus far.
One application for this technology is to use modeling of healthy human organs to test for toxicity. As the liver is critical in drug metabolism and toxicity, a liver tissue chip system is an ideal model. This system was designed to provide adequate oxygenation and drug distribution to make a functional liver model from a suspension culture of hepatocytes. Typical liver functions observed in the MPS, like glucose metabolism, better match in vivo conditions when compared to traditional in vitro culturing methods. Dr. Cirit’s team used this tissue chip to test clinically relevant parameters in response to multiple drugs to show that the system can predict drug responses of a variable human population. In a different MPS for proximal tubule injury in the kidney, different doses of a variety of drug were used to observe toxicity responses over 10 days, which is longer than what can be performed in traditional in vitro assays. This information on biomarker response to drugs can be combined with QSP modeling for pharmacokinetics and pharmacodynamics (PK/PD) to determine the proper therapeutic window for that drug.
In a further test of physiological relevance, an expanded system of multiple MPS linked together was used to look at the responses of six established drugs. This multi-organ MPS used physiologically appropriate cardiac output and organ sizes for proper circulation of the drug and its metabolites and is able to use simulations of intravenous and oral dosing. This system was maintained for up to four weeks, allowing for long-term profiles of biomarker response and pharmacokinetic parameters like the maximum serum concentration of the drug.
Sarah Yunes (left), Dr. Cirit (center), and Mahdiar Sadeghi (right) during the interview
In our interview, Dr. Cirit says that the next big step for tissue chip technology is disease modeling to perform preclinical assays showing the effect of the drug on the disease state. For some diseases that are more specific to one organ, like cancer or certain diseases caused by single gene mutations, a tissue chip simulating one organ is likely sufficient for showing efficacy. For diseases that are more systemic, multiple tissue chips will need to be linked together. There are some challenges to replacing animal studies completely, however. As of now, the data on this technology needs to be strengthened to show that these chips can replace the well-established animal-based methodologies. Dr. Cirit asks “how can we replace the assays” currently done in animals, like PK/PD studies often done in rats. In this way, the technology can move “from assay to assay to reduce animal studies” before replacing them. QSP has an important place in advancing the technology as the QSP models can be used to put the data from the tissue chips into the greater clinical context and using both combined to make better decisions about how to treat patients. When he’s not busy working, Dr. Cirit enjoys traveling and having “different cultural experiences”.
Dr. Cirit’s talk was followed by a mixer event where community members discussed and socialized over food and drinks. Check out the May Event: The Photo Blog for more details and highlights.
We would like to thank Novartis for sponsoring the event and the CIC for sponsoring the venue.
Boston! Our upcoming event “Innovation in Biopharma and Digital Health” is on June 19th. This June event will be put on in collaboration with World Pharma Week (WPW). The WPW includes four different congresses: 1) the Biomarker World Congress, 2) the World Preclinical Congress, 3) the inaugural Immuno-Oncology (IO) Pharma Congress, and 4) the inaugural Digital Health Pharma Congress. Boston QSP guests are invited to the “Fourth of July” themed reception from 5pm to 6:15 pm, provided by the Digital Health Pharma Congress and the Cambridge Healthcare Institute. Stay tuned for more details. To RSVP (free), please click here.
As an added bonus, anyone who RSVPs for our next event gets a free exhibit hall pass, which includes access to networking with 1,500 attendees during receptions and coffee breaks, plenary keynote sessions, 130+ scientific posters, 30+ roundtable breakout discussions, and 130+ Exhibiting Companies from June 18 through June 20. In addition, anyone who RSVPs for our next event also receives a discount code for 50% off full admission to the World Pharma Week event. Don’t miss it!