U.S. flag An official website of the United States government

On Oct. 1, 2024, the FDA began implementing a reorganization impacting many parts of the agency. We are in the process of updating FDA.gov content to reflect these changes.

U.S. Food and Drug Administration
  1. Home
  2. Science & Research
  3. Science and Research Special Topics
  4. Advancing Regulatory Science
  5. Microphysiological Systems for the Evaluation of Drug-induced Liver Injury
  1. Advancing Regulatory Science

Microphysiological Systems for the Evaluation of Drug-induced Liver Injury

CERSI Collaborators: Hongbing Wang, PhD; Linhao Li, PhD; Sara Geriesh

FDA Collaborators: Nakissa Sadrieh, PhD; Minjun Chen, PhD

CERSI In-Kind Collaborators: Scott Heyward, BioIVT ; Karissa Cottier, PhD (Hepatomune), in vitro toxicology; and Jeannemarie Gaffney (Hepatomune).

Project Start: January 9, 2024

Regulatory Science Challenge

Drug-indued liver injury (DILI) can lead to severe liver damage and often causes drug development to stop. Although much attention has been paid to this drug safety concern, it remains a challenging problem because existing test methods, and especially animal studies, cannot adequately predict all causes of DILI. Thus, there is great interest in developing and validating better lab-based models which will help to predict DILI more accurately. In this project, we will test selected drugs known to cause liver injury along with similar drugs that do not cause liver injury, to evaluate an alternative non-animal model called Hepatomune, which mimics the liver environment, including human liver cells and immune cells in a specialized system. We shall compare the Hepatomune model with a less complex model called Hepatopac, which does not contain the immune system cells, because investigators believe that the presence of the immune cells will greatly add to the predictive value of these non-animal models of liver injury.

Project Description and Aims/Goals

This project focuses on the following primary goals:

  1. Select drug pairs to be used as model drugs to evaluate the predictability of DILI
    1. Drug selections: A drug pair is composed of two drugs with similar molecular structure and pharmacological effects but different liver toxicity in humans. Investigators will select three drug pairs to test in this project.
  2. Determine the hepatotoxicity profiles of selected drugs in HEPATOPAC/HEPATOMUNE models. We will:
    1. Determine the dose causing 50% cell death (IC50) of each drug in the HEPATOPAC and HEPATOMUNE models.
    2. Assess the extent to which the drugs selected affect typical liver functions in each model, such as the expression of key drug-metabolizing enzymes and transporters.
    3. Evaluate the extent to which the drugs selected can cause inflammatory responses which we will measure using appropriate markers of inflammation.

Anticipated Outcomes/Impact

This project is expected to provide insight into the development of best practices for the use of novel non-animal methods aimed at evaluating specific types of liver injury caused by drug treatment, which currently cannot be adequately predicted using existing models. Additionally, the results from this project will help to support the ultimate qualification of methods to aid pharmaceutical companies to more broadly use more non-animal methods in drug development. Finally, this project will support the development of FDA guidance for Industry, which will describe best practices, as well as how to interpret results from these non-animal-based methods.

Back to Top