Clinical efficacy and safety of remdesivir in patients with COVID-19: a systematic review and network meta-analysis of randomized controlled trials

Lai, Chih‐Cheng; Chen, Chao-Hsien; Chen, Ming-Fong; Chen, Kuang-Hung; Wang, Yahui; Hsueh, Po-Ren

doi:10.1093/jac/dkab093

Cited by 75 publications

(60 citation statements)

References 34 publications

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“…In vitro testing has also shown that RDV has activity against SARS-CoV-2 and data from literature described the possible benefits of early initiation of RDV, especially within 10 days from clinical symptom onset, in term of shorter time to recovery, along with low risk of side effects or adverse events compared to placebo or comparators [9][10] . Despite controversial data on the efficacy of RDV in the context of COVID-19 infection, RDV remains one of the main promising compound in the setting of viral infections as Ebola, Marburg or Mers-CoV viruses [11][12] .…”

Section: Introductionmentioning

confidence: 99%

Real‐life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID‐19 pneumonia

Corcione

Nicolò

Montrucchio

et al. 2021

Brit J Clinical Pharma

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Remdesivir is one of the most encouraging treatments against SARS‐CoV‐2 infection. After intravenous infusion, RDV is rapidly metabolized (T 1/2 1h) within the cells to its active adenosine triphosphate analogue form (GS‐443902) and, then, it can be found in plasma in its nucleoside analogue form (GS‐441524). In this real life study we describe the Remdesivir and GS‐441524 concentrations at 3 time points in nine ICU patients, through a validated UHPLC‐MS/MS method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half‐life of GS‐441524. The mean C min , C max , AUC 0–24 , were < 0.24 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively for RDV and GS‐441524. Three out of nine patients achieved a C max > 2610 ng/mL and 140 ng/mL and AUC 0–24 > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS‐441524, respectively. The mean T1/2 value for GS‐441524 was 26.3 h. Although the low number of patients, these data can represent an interesting preliminary report of the variability of RDV and GS‐441524 concentrations in real‐life ICU setting.

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Section: Introductionmentioning

confidence: 99%

Real‐life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID‐19 pneumonia

Corcione

Nicolò

Montrucchio

et al. 2021

Brit J Clinical Pharma

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“…The observation that there is room for improvement in the dosing regimen is in line with clinical trials that report a shorter time to recovery [ 1 , 48 ], newer meta-analyses that support a slightly reduced mortality [ 7 ] and recent findings that the viral load declines more quickly in patients receiving remdesivir [ 11 ]. We therefore would like to argue specifically for more dose-ranging and dose-fractionation trials.…”

Section: Discussionmentioning

confidence: 71%

Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?

Conway

Wiesch

2021

Pharmaceutics

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The antiviral remdesivir has been approved by regulatory bodies such as the European Medicines Agency (EMA) and the US Food and Drug administration (FDA) for the treatment of COVID-19. However, its efficacy is debated and toxicity concerns might limit the therapeutic range of this drug. Computational models that aid in balancing efficacy and toxicity would be of great help. Parametrizing models is difficult because the prodrug remdesivir is metabolized to its active form (RDV-TP) upon cell entry, which complicates dose–activity relationships. Here, we employ a computational model that allows drug efficacy predictions based on the binding affinity of RDV-TP for its target polymerase in SARS-CoV-2. We identify an optimal infusion rate to maximize remdesivir efficacy. We also assess drug efficacy in suppressing both wild-type and resistant strains, and thereby describe a drug regimen that may select for resistance. Our results differ from predictions using prodrug dose–response curves (pseudo-EC50s). We expect that reaching 90% inhibition (EC90) is insufficient to suppress SARS-CoV-2 in the lungs. While standard dosing mildly inhibits viral polymerase and therefore likely reduces morbidity, we also expect selection for resistant mutants for most realistic parameter ranges. To increase efficacy and safeguard against resistance, we recommend more clinical trials with dosing regimens that substantially increase the levels of RDV-TP and/or pair remdesivir with companion antivirals.

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“…Parallelly, Goldman et al compared a 5-day regimen of remdesivir versus a 10-day course and despite noticing a trend toward better outcomes in patients receiving it for 5 days, the differences were not statistically significant [ 47 ]. These results have been compared with those of a meta-analysis published online in March 2021, where five of the RCTs included in this systematic review are analysed [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the one hand, this meta-analysis reveals that those who received a 5-day remdesivir therapy had greater clinical improvement compared to those in the control group (OR = 1.68; 95% CI = 1.18–2.40). On the other hand, no statistically significant differences were observed between those with a 10-day remdesivir regimen and those receiving placebo (OR = 1.23; 95% CI = 0.90–1.68) [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

Antiviral Therapeutic Approaches for SARS-CoV-2 Infection: A Systematic Review

2021

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Background: Due to the lack of an etiologic treatment for SARS-CoV-2 and the difficulties involved in developing new drugs, some drugs already approved for other diseases or with efficacy against SARS and MERS, have been used in patients with COVID-19. This systematic review aims to summarize evidence on the efficacy and safety of five antivirals applied to patients with COVID-19, that have proven to be effective either in vitro studies or in studies on SARS-CoV and MERS.; Methods: An intensive search of different databases (Pub Med, WoS, MEDLINE and Cochrane COVID-19 Study Register) has been carried out until the end of April 2021. This systematic review has been conducted according to the PRISMA statement. From each of the included studies, the characteristics of the intervention and comparison groups, demographic data and results were extracted independently; Results: Remdesivir is well tolerated and helps to accelerate clinical improvement but is ineffective in reducing mortality. Favipiravir is safe and shows promising results regarding symptom resolution but does not improve viral clearance. The use of lopinavir/ritonavir has been associated with an increased risk of gastrointestinal adverse events and it has not proven to be effective. No significant differences were observed between patients treated with ribavirin or umifenovir and their respective control groups; Conclusions: Remdesivir and favipiravir are well tolerated and effective in accelerating clinical improvement. This systematic review does not support the use of lopinavir/ritonavir, ribavirin and umifenovir in hospitalized patients with COVID-19.

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Clinical efficacy and safety of remdesivir in patients with COVID-19: a systematic review and network meta-analysis of randomized controlled trials

Cited by 75 publications

References 34 publications

Real‐life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID‐19 pneumonia

Real‐life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID‐19 pneumonia

Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?

Antiviral Therapeutic Approaches for SARS-CoV-2 Infection: A Systematic Review

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