Abstract
Remdesivir has displayed pharmacological activity against SARS-CoV-2. However, no pharmacometabolomics (PM) or correlation analysis with pharmacokinetics (PK) was revealed. Rats were intravenously administered remdesivir, and a series of blood samples were collected before and after treatment. Comprehensive metabolomics profile and PK were investigated and quantitated simultaneously using our previous reliable HPLC-MS/MS method. Both longitudinal and transversal metabolic analyses were conducted, and the correlation between PM and PK parameters was evaluated using Pearson’s correlation analysis and the PLS model. Multivariate statistical analysis was employed for discovering candidate biomarkers which predicted drug exposure or toxicity of remdesivir. The prominent metabolic profile variation was observed between pre- and posttreatment, and significant changes were found in 65 metabolites. A total of 15 metabolites—12 carnitines, one N-acetyl-D-glucosamine, one allantoin, and one corticosterone—were significantly correlated with the concentration of Nuc (active metabolite of remdesivir). Adenosine, spermine, guanosine, sn-glycero-3-phosphocholine, and l-homoserine may be considered potential biomarkers for predicting drug exposure or toxicity. This study is the first attempt to apply PM and PK to study remdesivir response/toxicity, and the identified candidate biomarkers might be used to predict the AUC and Cmax, indicating capability of discriminating good or poor responders. Currently, this study originally offers considerable evidence to metabolite reprogramming of remdesivir and sheds light on precision therapy development in fighting COVID-19.
Highlights
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat for the global health environment (Zhu et al, 2020)
In the face of the current global pandemic posed by SARS-CoV2 infection, there is an urgent necessitation to prompt a fervent search for effective therapy and to improve our knowledge of the metabolomic mechanism
Remdesivir, a nucleotide analog prodrug, which is metabolized into an analog of adenosine triphosphate (GS-441544, Nuc), has broad-spectrum activity against variety of viruses including Ebola, SARS-CoV-2, Middle East respiratory syndrome coronavirus (MERS-CoV), and COVID-19 (Lamb, 2020)
Summary
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat for the global health environment (Zhu et al, 2020). In the face of the current global pandemic posed by SARS-CoV2 infection, there is an urgent necessitation to prompt a fervent search for effective therapy and to improve our knowledge of the metabolomic mechanism. Even if Integration Analysis of Pharmacokinetics and Metabolomics of Remdesivir this pandemic will be possibly controlled in the few months, unexpected outbreaks and development of viral resistance to therapy due to virus mutations have exacerbated the already severe epidemic. Several therapeutic strategies (e.g., small molecular chemical antiviral drug (Costanzo et al, 2020), traditional Chinese medicine (Ren et al, 2020), and vaccines (Lurie et al, 2020)) are being employed to improve the ratio of benefit/risk of patients with COVID-19. Remdesivir has been granted emergency use authorization by the U.S Food and Drug Administration in November 2020 for hospitalized COVID-19 patients, and remdesivir may be considered a possible therapeutic option for COVID-19
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