Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients
Background:. Coronavirus disease 2019 (COVID-19) is a global pandemic that has caused more than 600 million cases and over six million deaths worldwide. Despite the availability of vaccination, COVID-19 cases continue to grow making pharmacological interventions essential. Remdesivir (RDV) is an FDA...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Health/LWW
2023-03-01
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| Series: | Hepatology Communications |
| Online Access: | http://journals.lww.com/10.1097/HC9.0000000000000034 |
| _version_ | 1811161602801532928 |
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| author | Kaiyan Liu Sydney Stern Emily L. Heil Linhao Li Rula Khairi Scott Heyward Hongbing Wang |
| author_facet | Kaiyan Liu Sydney Stern Emily L. Heil Linhao Li Rula Khairi Scott Heyward Hongbing Wang |
| author_sort | Kaiyan Liu |
| collection | DOAJ |
| description | Background:. Coronavirus disease 2019 (COVID-19) is a global pandemic that has caused more than 600 million cases and over six million deaths worldwide. Despite the availability of vaccination, COVID-19 cases continue to grow making pharmacological interventions essential. Remdesivir (RDV) is an FDA-approved antiviral drug for treatment of both hospitalized and non-hospitalized COVID-19 patients, albeit with potential for hepatotoxicity. This study characterizes the hepatotoxicity of RDV and its interaction with dexamethasone (DEX), a corticosteroid often co-administered with RDV for inpatient treatment of COVID-19.
Methods:. Human primary hepatocytes and HepG2 cells were used as in vitro models for toxicity and drug-drug interaction studies. Real-world data from hospitalized COVID-19 patients were analyzed for drug-induced elevation of serum ALT and AST.
Results:. In cultured hepatocytes, RDV markedly reduced the hepatocyte viability and albumin synthesis, while it increased the cleavage of caspase-8 and caspase-3, phosphorylation of histone H2AX, and release of ALT and AST in a concentration-dependent manner. Importantly, co-treatment with DEX partially reversed RDV-induced cytotoxic responses in human hepatocytes. Moreover, data from COVID-19 patients treated with RDV with and without DEX co-treatment suggested that among 1037 patients matched by propensity score, receiving the drug combination was less likely to result in elevation of serum AST and ALT levels (≥ 3 × ULN) compared to the RDV alone treated patients (OR = 0.44, 95% CI = 0.22–0.92, p = 0.03).
Conclusion:. Our findings obtained from in vitro cell-based experiments and patient data analysis provide evidence suggesting combination of DEX and RDV holds the potential to reduce the likelihood of RDV-induced liver injury in hospitalized COVID-19 patients. |
| first_indexed | 2024-04-10T06:17:02Z |
| format | Article |
| id | doaj.art-2380619583fe46a091bae04a9790017d |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-04-10T06:17:02Z |
| publishDate | 2023-03-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-2380619583fe46a091bae04a9790017d2023-03-02T06:30:57ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2023-03-0173e0034e003410.1097/HC9.0000000000000034HC90000000000000034Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patientsKaiyan Liu0Sydney Stern1Emily L. Heil2Linhao Li3Rula Khairi4Scott Heyward5Hongbing Wang6 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA 2 Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, Maryland, USA 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA 3 BioIVT, 1450 S Rolling Rd, Halethorpe, Maryland, USA 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USABackground:. Coronavirus disease 2019 (COVID-19) is a global pandemic that has caused more than 600 million cases and over six million deaths worldwide. Despite the availability of vaccination, COVID-19 cases continue to grow making pharmacological interventions essential. Remdesivir (RDV) is an FDA-approved antiviral drug for treatment of both hospitalized and non-hospitalized COVID-19 patients, albeit with potential for hepatotoxicity. This study characterizes the hepatotoxicity of RDV and its interaction with dexamethasone (DEX), a corticosteroid often co-administered with RDV for inpatient treatment of COVID-19. Methods:. Human primary hepatocytes and HepG2 cells were used as in vitro models for toxicity and drug-drug interaction studies. Real-world data from hospitalized COVID-19 patients were analyzed for drug-induced elevation of serum ALT and AST. Results:. In cultured hepatocytes, RDV markedly reduced the hepatocyte viability and albumin synthesis, while it increased the cleavage of caspase-8 and caspase-3, phosphorylation of histone H2AX, and release of ALT and AST in a concentration-dependent manner. Importantly, co-treatment with DEX partially reversed RDV-induced cytotoxic responses in human hepatocytes. Moreover, data from COVID-19 patients treated with RDV with and without DEX co-treatment suggested that among 1037 patients matched by propensity score, receiving the drug combination was less likely to result in elevation of serum AST and ALT levels (≥ 3 × ULN) compared to the RDV alone treated patients (OR = 0.44, 95% CI = 0.22–0.92, p = 0.03). Conclusion:. Our findings obtained from in vitro cell-based experiments and patient data analysis provide evidence suggesting combination of DEX and RDV holds the potential to reduce the likelihood of RDV-induced liver injury in hospitalized COVID-19 patients.http://journals.lww.com/10.1097/HC9.0000000000000034 |
| spellingShingle | Kaiyan Liu Sydney Stern Emily L. Heil Linhao Li Rula Khairi Scott Heyward Hongbing Wang Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients Hepatology Communications |
| title | Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients |
| title_full | Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients |
| title_fullStr | Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients |
| title_full_unstemmed | Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients |
| title_short | Dexamethasone mitigates remdesivir-induced liver toxicity in human primary hepatocytes and COVID-19 patients |
| title_sort | dexamethasone mitigates remdesivir induced liver toxicity in human primary hepatocytes and covid 19 patients |
| url | http://journals.lww.com/10.1097/HC9.0000000000000034 |
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