Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
Hepatol Commun. 2023 Feb 20;7(3):e0034. doi: 10.1097/HC9.0000000000000034. eCollection 2023 Mar 1.
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.
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.
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).
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.
2019 年冠状病毒病（COVID-19）是一种全球性大流行疾病，已在全球范围内导致超过 6 亿例病例和超过 600 万人死亡。尽管有疫苗可用，但 COVID-19 病例仍在继续增加，因此药物干预至关重要。瑞德西韦（RDV）是一种获得美国食品和药物管理局（FDA）批准的抗病毒药物，可用于治疗住院和非住院的 COVID-19 患者，但有潜在的肝毒性。本研究旨在描述 RDV 的肝毒性及其与地塞米松（DEX）的相互作用，DEX 常与 RDV 联合用于 COVID-19 住院患者的治疗。
使用人原代肝细胞和 HepG2 细胞作为毒性和药物相互作用研究的体外模型。分析住院 COVID-19 患者的真实世界数据，以评估药物引起的血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）升高情况。
在培养的肝细胞中，RDV 显著降低了肝细胞活力和白蛋白合成，同时以浓度依赖性方式增加了半胱氨酸天冬氨酸蛋白酶-8 和半胱氨酸天冬氨酸蛋白酶-3 的切割、组蛋白 H2AX 的磷酸化以及 ALT 和 AST 的释放。重要的是，DEX 共同治疗部分逆转了 RDV 诱导的人肝细胞细胞毒性反应。此外，接受 RDV 联合或不联合 DEX 治疗的 COVID-19 患者的数据表明，在 1037 名按倾向评分匹配的患者中，与单独使用 RDV 治疗的患者相比，接受药物联合治疗不太可能导致血清 AST 和 ALT 水平升高（≥3×正常值上限）（比值比=0.44，95%置信区间=0.22-0.92，p=0.03）。
本研究通过体外细胞实验和患者数据分析获得的结果提供了证据，表明 DEX 和 RDV 的联合使用有可能降低住院 COVID-19 患者中 RDV 引起的肝损伤的可能性。
