On May 1, 2020, after review of yet unpublished data from available clinical trials, the US Food and Drug Administration issued an emergency use authorization (EUA) to permit the use of remdesivir, a nucleotide analog that inhibits viral RNA-dependent RNA polymerase (RDRP), for treatment of adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). EUA was granted after an interim analysis of 606 recoveries in the randomized, placebo-controlled National Institute of Allergy and Infectious Diseases Adaptive Covid-19 Treatment Trial (n=1063 participants from 47 United States sites and 21 international sites). Remdesivir reduced the median time to recovery (11 versus 15 days; hazard ratio, 1.31; 95% confidence interval, 1.12 to 1.54; P<0.001) compared with placebo, and overall mortality among patients treated with remdesivir was 8.0% compared with 11.6% among those treated with placebo (P=0.59).1 Notably, patients with severe AKI and ESKD were excluded from this and all other remdesivir trials on the basis of eGFR cutoffs (either 50 or 30 ml/min per 1.73 m2) (Table 1). As a result, the EUA fact sheet for health care providers states the following.1The pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment. Adult and pediatric patients (>28 days old) must have creatinine clearance determined and full-term neonates (≥7 days to ≤28 days old) must have serum creatinine determined before dosing. Remdesivir is not recommended in adults and pediatric patients (>28 days old) with eGFR less than 30 mL per minute or in full-term neonates (≥7 days and ≤28 days old) with serum creatinine ≥1 mg/dL unless the potential benefit outweighs the potential risk. (emphasis added)
Summary of available clinical trial data
Severe COVID-19 infection leads to AKI in up to 20%–40% of critically ill patients, and the ESKD population has a higher risk for exposure and is at increased risk for severe infection. Yet, many of these patients may not be considered for treatment with this potentially beneficial agent. Here, we review what is known about remdesivir and the potential risks of its administration in patients with impaired kidney function.
Remdesivir
Replication of the single-stranded RNA genome of severe acute respiratory syndrome coronavirus 2 depends on an RDRP. Remdesivir is a prodrug that, after metabolized to remdesivir triphosphate, acts as an analog of ATP, competing for incorporation by RDRP and interfering with viral RNA replication (Figure 1). Originally developed as an investigational agent for Ebola, it has activity against severe acute respiratory syndrome coronavirus 2 in vitro and in animal models.4,5 Remdesivir has a molecular weight of 602.6 g/mol with limited water solubility. It is administered intravenously at a dose of 200 mg once followed by 100 mg daily for a total of 5–10 days in adults and children ≥40 kg. Pharmacokinetic data among individuals with normal kidney function demonstrated that remdesivir and its active metabolite are predominantly (74%) renally eliminated. The plasma t1/2 of parent remdesivir is short (1–2 hours), but the t1/2 of the active metabolite remdesivir triphosphate is approximately 20–25 hours,4 with wide distribution to most tissues.6,7 Concerns about the drug’s potential toxicity in patients with kidney disease relate both to remdesivir’s actions and to the potential accumulation of its sulfobutylether-β-cyclodextrin (SBECD) carrier.
Mechanism of action of remdesivir. Remdesivir triphosphate leads to delayed chain termination after three additional bases have been added.
Risks of Remdesivir
Because remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases, it is considered to have low potential for mitochondrial toxicity.1 Although other nucleotide/nucleoside antivirals (i.e., tenofovir) can lead to mitochondrial injury in renal tubular epithelial cells, kidney toxicity occurs after prolonged exposure and therefore, would be extraordinarily rare to occur within a 5- or 10-day therapy course.8 Notably, toxicology studies in rhesus monkeys showed kidney injury and casts at doses of 5, 10, and 20 mg/kg for 7 days, considerably higher than the EUA dose.1 Available data from a single randomized, controlled trial in COVID-19 did not demonstrate an increased risk of renal adverse events in patients randomized to receive remdesivir.3 In addition, significant renal adverse events were not reported when remdesivir was used in a clinical trial for Ebola.9
Transaminase elevations have been reported in healthy volunteers and COVID-19–infected patients receiving remdesivir. Under the EUA, liver function tests must be monitored daily, and remdesivir is discontinued in patients with alanine aminotransferase more than five times the upper limit of normal.1 Infusion-related reactions have also been reported.
Risk of SBECD Carrier Accumulation
Because remdesivir has limited water solubility, the intravenous preparation contains the vehicle SBECD. SBECD is a large, cyclic oligosaccharide that is predominantly excreted through glomerular filtration with a t1/2 of elimination of <2 hours in patients with normal kidney function.10 Animal studies have associated SBECD accumulation with liver necrosis and renal tubule obstruction,11 which occurred in animals at doses 50- to 100-fold higher than expected for a 5- to 10-day remdesivir course. Each 100 mg of lyophilized powder and solution of remdesivir contain 3 and 6 g of SBECD, respectively, well below the maximum recommended safety threshold dose of 250 mg/kg per day of SBECD.
Much of what is known about the pharmacokinetics and clinical effects of SBECD in kidney failure is gleaned from literature of intravenous voriconazole, which also uses this carrier. Although oral voriconazole is preferred for patients with renal failure, intravenous therapy may be necessary in patients with invasive fungal infections who are critically ill with poor gut perfusion that limits oral absorption. In this setting, short courses are generally well tolerated, without significant adverse events noted despite documented accumulation of SBECD above levels in patients with normal kidney function.10–14 Further, SBECD is readily removed by continuous RRT and hemodialysis, and significant accumulation only occurs in patients when dialysis is held for prolonged periods.12 Although SBECD exposure is higher than in patients with normal kidney function, RRT seems to keep this exposure within a limit that is generally considered safe. Although numbers are limited, liver function test elevation attributed to SBECD use in patients with kidney failure was rare and transient.10,13
Conclusive data on the safety of remdesivir among individuals with eGFR<30 ml/min per 1.73 m2 are lacking. Nevertheless, the limited duration of treatment (5–10 days) and relatively low concentration of SBECD carrier suggest that its benefits may outweigh risk in select patients with eGFR<30 ml/min per 1.73 m2. Patients without underlying liver disease who are expected to undergo continuous or intermittent dialysis or those with AKI expected to be transient may be the best initial candidates to receive remdesivir. Ultimately, patients or their surrogates should be informed of the lack of information in patients with eGFR<30 ml/min per 1.73 m2 and should consent for use in this emergency setting.
Evaluating treatments for patients with COVID-19 who have AKI and ESKD is a major unmet clinical need given that these patients are at high risk of suffering excess morbidity and mortality. Of note, favipiravir, another RDRP inhibitor under investigation for treatment of COVID-19, is also predominantly excreted through the urine; thus, patients with eGFR<20 ml/min per 1.73 m2 are also excluded from clinical trials (NCT04358549). Although the World Health Organization’s Solidarity trial, which allows clinician discretion in enrolling patients,15 may include some patients with kidney disease, an urgent need remains for dedicated trials in patients with COVID-19 who have eGFR<30 ml/min per 1.73 m2. Although this is not a unique example of the exclusion of patients with kidney disease from clinical trials assessing critical treatments,16 the magnitude and pace of the current pandemic and the vulnerability of these patients create an immediate call to action for trials and systematic retrospective studies that can inform clinical decision making and increase access to a potentially life-saving therapy in this patient population.
Disclosures
A. Kim has served on an advisory board for Biomarin, Inc. (gene therapy). M. Sise discloses personal fees and participation in scientific advisory boards for Gilead in the area of viral hepatitis. All remaining authors have nothing to disclose.
Funding
M. Sise reports funding from National Institute of Diabetes and Digestive and Kidney Diseases grant DK117014.
Acknowledgments
The authors thank Xavier Vela Parada for medical illustration of Figure 1.
This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
- Copyright © 2020 by the American Society of Nephrology
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