Metabolism-based DDI and Liver Toxicity of Drug Candidates in COVID-19 Treatment

CERSI P.I. and Collaborator: Hongbing Wang, Ph.D., UMB School of Pharmacy

FDA SME and Collaborator: Shiew-Mei Huang Ph.D., CDER, FDA

 

In the U.S. alone, confirmed COVID-19 cases reached 4,339,997 with 148,866 deaths as of July 29th, 2020 (CDC). As of publication, treatment relies primarily on repurposing of existing drugs approved for other clinical usage or investigational compounds that have not been fully evaluated for their safety and efficacy. Many patients who are elderly and/or have pre-existing conditions such as cardiovascular disease and diabetes, often take multiple medications simultaneously. Thus, the potential for unexpected drug-drug interactions and side toxicity in these vulnerable COVID-19 patients is high. Given that liver is the main organ responsible for drug metabolism and drug-induced liver injury is one of the top reasons leading to drug development failure, we will use a three-dimensional (3D) human

liver model to investigate the potential liver toxicity and drug-drug interactions of drug candidates used in the current COVID-19 treatment.

 

Preclinical evaluation of drug safety and efficacy is pivotal in drug development. While studies in animal model provide key preclinical findings, species-difference between humans and animals has decreased the value of these data particularly related to toxicity evaluation. 3D human cell-based models provide improved physiologically relevance and offer great potentials for accurate prediction of drug risks and effectiveness. We have successfully developed and validated a 3D human liver spheroid co-culture model. With proper incorporation of various types of liver cells, this 3D spheroid model maintains robust liver functions for longer periods of time compared to 2D models. We will use this 3D human liver spheroid model to 1) assess induction of major drug-metabolizing enzymes by 15 COVID-19 drugs; and 2) determine the potential liver toxicity of this panel of drugs. Successful completion of these studies is expected to provide human relevant preclinical data regarding potential metabolism-based drug-drug interaction and liability of liver toxicity associated with COVID-19 drugs.