CERSI Collaborators: Hongbing Wang, PhD; Kaiyan Liu, PhD; Linhao Li, PhD; Emily Heil, Pharm D; Sydney Stern, MS (University of Maryland School of Pharmacy)

FDA Collaborators: Shiew-Mei Huang, PhD; Qi Liu, PhD; Lei Zhang, PhD (CDER); Marie Bradley, PhD, MPharm, MPH (OSE/CDER), Paul Brown, PhD

Project Start Date: June 9, 2020

Project Start Date: August 30, 2023

Regulatory Science Challenge

In the past several years, COVID-19 has contributed to millions of deaths worldwide. In the United States alone, total hospitalized COVID-19 cases have reached 6,452,832 with 1,151,435 deaths as of November 6, 2023, per CDC’s COVID Data Tracker. Even with the availability of vaccines, treatment represents an essential step to prevent hospitalization and decrease death from COVID-19. Remdesivir is an FDA-approved antiviral drug for treatment of hospitalized COVID-19 patients, but this drug can be potentially toxic to the liver. This project studies the toxicity of remdesivir on the liver as well as the effect of dexamethasone, another drug often used together with remdesivir in treating COVID-19 infections, on remdesivir induced liver injury. This project will study data from two sources: in vitro human liver cell-based models (this type of model is set up in an “artificial” environment in the lab, as opposed to studying liver tissue inside the living body) as well as real-world patient data (data obtained from sources like medical records and health insurance claims).

Project Description and Goals

This project focuses on these primary goals:

1. Determine the induction of major drug-metabolizing enzymes by ten COVID-19 drugs in a 3-dimensional (3D) human liver model.
2. Determine the potential toxicity of ten COVID-19 drugs in a 3D human liver model.
3. Examine if dexamethasone use may interfere with the effects of remdesivir, in COVID-19 treatment.

Research Outcomes/Results

In Aim 1, Researchers tested seven COVID-19 drugs for their potential induction of major drug-metabolizing enzymes. The toxicity in human liver cells of these drugs was also evaluated. With the advances in COVID-19 treatment, some of these drugs initially in the trials are no longer used to treat patients, thus our research has focused on remdesivir, the first FDA-approved drug for COVID-19 treatment.

Aim 2 focused on the toxicity of remdesivir and established its toxicity responses in different human liver cell models. The interaction between remdesivir and dexamethasone was also investigated. Researchers showed that in human liver cells, remdesivir markedly reduced the cell viability while increasing apoptosis (cell death) and DNA damage. Importantly, when dexamethasone was included, remdesivir-induced liver cell damage was reduced in the human liver cells.

In Aim 3, real-world data from COVID-19 inpatients treated with remdesivir with and without dexamethasone at the same time suggested that patients receiving the drug combination were less likely to show an increase in two biomarkers (a biological molecule that is an indicator of disease or other conditions, normal or abnormal) for liver injury. While additional clinical trials are required to eventually confirm University of Maryland Centers of Excellence in Regulatory Science and Innovation (M-CERSI)’s current real-world data, M-CERSI’s findings suggest a combination of dexamethasone and remdesivir may reduce the likelihood of remdesivir-induced liver injury in hospitalized COVID-19 patients.

Research Impacts

The liver is the major organ in the body that reduces the toxicity of drugs and is often challenged by various drugs. In this project, we uncover that dexamethasone use may reduce remdesivir-induced liver toxicity. This finding suggests that in addition to reducing respiratory symptoms in hospitalized COVID-19 patients, the combination of remdesivir and dexamethasone may provide an alternative safety benefit by reducing the likelihood of liver toxicity from remdesivir.

Publications

1. Liu K, Stern S, Heil EL, Li L, Khairi R, Heyward S, and Wang H. (2023) Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients. Hepatol Commun. 2023 Feb; 7(3):e0034. PMID: 36809346.


2. Liu K, Li L, Heyward S, Liu Q, Zhang L, Brown P, He L, Huang S, and Wang H. (2023) Mechanisms underlying dexamethasone protection of remdesivir-induced hepatotoxicity. In preparation for submission.