Vincent Peyko, PharmD, BCPS (AQ-ID)
Clinical Pharmacy Specialist – Emergency Medicine
Mercy Health – St. Elizabeth’s Boardman Hospital
Boardman, Ohio
Absurdities often exist in health care. We become hyperfocused on treating or preventing one outcome in a particular way, yet may be entirely oblivious when treating or preventing that same outcome from another angle. A perfect example is vancomycin versus vancomycin plus piperacillin-tazobactam (PTZ). Pharmacists and physicians spend countless hours trying to dose vancomycin appropriately for efficacy while preventing acute kidney injury (AKI). After vancomycin, PTZ is the most used antibiotic for hospital-onset infections.1 Vancomycin combined with PTZ is a very common IV empiric combination therapy—even a sepsis admission prerequisite—for many infections. Most clinicians do not bat an eye at initiating this combination, although it carries a substantial risk for AKI compared with other equitable options.2 So on one end, clinicians work tirelessly to prevent AKI by appropriately dosing vancomycin, but they entirely ignore whether that vancomycin is combined with PTZ. This is an absurdity. If A=B and B=C, then A should equal C, right? Whether it’s the status quo, groupthink, or just blind faith, health care is littered with these absurdities.
Another absurdity is that many health care providers appear completely comfortable using drugs in patient populations for which little to no data or negative data exist. Morbidly obese patients are sent home from emergency departments with apixaban to treat their deep vein thromboses; histamine H2 receptor antagonists are almost always part of anaphylaxis cocktails; providers still think antibiotics cure acute bronchitis or give nitrofurantoin to 90-year-olds with bad kidneys to treat urinary tract infections; and it is not uncommon to see prescribers order statins or drugs that “have not been studied” for patients with impaired renal function. Why does such complacency exist in some situations with no or negative data versus others?
With the arbitrary nature of some absurdities, should there be so much apprehension to administer remdesivir to patients with impaired renal function? Could this mindset be preventing a substantial patient population from receiving a potential option to treat COVID-19?
Remdesivir and the Emergency Use Authorization
Remdesivir, a nucleoside analog prodrug first developed in response to Ebola, inhibits viral replication by competing with endogenous nucleotides for incorporation into replicating viral RNA through RNA-dependent RNA polymerase.3 A nonstructural protein of this polymerase, nsp12, is highly conserved among coronaviruses, making it an attractive target for broad-spectrum antiviral drugs.3 This broad-spectrum activity against coronaviruses has prioritized the inclusion of remdesivir in many COVID-19 clinical trials.3 Remdesivir has been used to treat COVID-19 in the United States since late January 2020, and currently 51 studies are registered at ClinicalTrials.gov evaluating this use.4,5
Comparisons of remdesivir and placebo have yielded variable results, although the largest clinical trial (ACTT-1) demonstrated that remdesivir reduced time to recovery in patients hospitalized with COVID-19 versus placebo.6,7 These results were promising enough for the FDA to issue an emergency use authorization (EUA) for remdesivir.8 The EUA states that remdesivir is not recommended in patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min unless the potential benefits outweigh the risk.8 Without utilization data on patients with acute or chronic kidney injury, remdesivir may not be considered, leaving this patient population without the opportunity to receive a potentially beneficial treatment.9 But, aren’t the words “benefit outweighs risk” very important? Shouldn’t benefits outweigh risks for all patients, including those with normal renal function? Or any patient given any drug or any treatment?
Specific to remdesivir, what are the risks in patients with an eGFR of less than 30 mL/min and what are the potential benefits? By understanding both, providers can perform a risk-benefit analysis and make a decision.
Risks of Remdesivir With Impaired Kidney Function
Severe COVID-19, in and of itself, may lead to acute kidney injury in 20% to 40% of critically ill patients.9 There is no evidence to indicate remdesivir is more harmful in patients with impaired renal function. The safety and efficacy of remdesivir have not been studied in these patient populations.8 There are no published case reports on the topic, so all we can do is discuss theory. The largest randomized, double-blind, placebo-controlled trial of remdesivir did not demonstrate increased renal toxicity in patients receiving remdesivir compared with those given placebo.6 Renal adverse events (AEs) were not reported when remdesivir was studied in Ebola patients.10 Unfortunately, a lack of negative data does not make for positive data. The lack of safety data has led the FDA to recommend that providers weigh the risks versus benefits of using remdesivir in this patient population.8
Remdesivir should pose a low potential for mitochondrial toxicity because it is a weak inhibitor of mammalian DNA and RNA polymerases.9 Other nucleotide/nucleoside antivirals can lead to mitochondrial toxicity in the renal tubules with prolonged exposure, but toxicity from 5- to 10-day courses of therapy would be considered rare.9
Less than 10% of remdesivir is excreted renally.3 However, 49% of a remdesivir metabolite (GS-441524) has been recovered in urine.3 Thus, theoretically, accumulation of this metabolite may occur in patients with impaired renal function, although the clinical significance of this accumulation remains unknown.3
Sulfobutylether-beta-cyclodextran (SBECD), an agent used to improve the solubility of remdesivir, is excreted predominantly through glomerular filtration; hence, accumulation and theoretical toxicity is hypothesized in patients with impaired renal function.3,9 Animal studies in rats and dogs have demonstrated mild kidney toxicity with SBECD doses approximately 50-fold greater than those administered typically in humans.11 The IV formulation of the azole antifungal voriconazole contains SBECD, and much of what is known about the pharmacokinetics and clinical effects of SBECD in patients with renal failure has been derived from data on voriconazole.9 Hemodialysis significantly removes SBECD and reduces SBECD levels.12 SBECD may accumulate in patients with impaired renal function, but there is no evidence this accumulation leads to any AEs.9,12,13
Each 100-mg vial of remdesivir lyophilized powder contains 3 g of SBECD and each 100-mg vial of remdesivir solution contains 6 g of SBECD, both of which would be far below the recommended safety threshold of 250 mg/kg of SBECD per day.9
Although patients who had an eGFR of less than 30 mL/min or were on hemodialysis were excluded, there was no significant difference in AEs between patients given remdesivir versus placebo in both of the published randomized, double-blind, placebo-controlled trials evaluating remdesivir.3,6,7 Nausea, hypokalemia, and headache were more common in patients receiving remdesivir than those given placebo in the open-label, randomized trial comparing different durations of remdesivir versus placebo, although serious AEs were more common in those receiving placebo.14
Although increased risks may exist with remdesivir treatment in patients who have an eGFR of less than 30 mL/min or are on hemodialysis, there are no data to confirm or negate any such risks in this patient population.
Benefits of Remdesivir
The efficacy of remdesivir remains unclear. To date, there are 2 published randomized, double-blind trials and 1 randomized, open-label study comparing remdesivir with placebo.6,7,14 A Chinese study, conducted between February 6 and March 12, 2020, evaluated 237 patients randomly assigned to receive 10 days of remdesivir or placebo.7 The investigators found no significant difference in clinical benefits between the groups, although there was a numerically shorter time to clinical improvement with remdesivir versus placebo.7 In the multinational ACTT-1 study evaluating 1,059 patients randomly assigned to receive 10 days of remdesivir or placebo, which was conducted between February 21 and April 19, 2020, remdesivir was superior to placebo in shortening time to recovery for adults hospitalized with COVID-19.6 Patients receiving remdesivir had a median time to recovery of 11 days, versus 15 days for patients given placebo (P<0.001).6 A recently published study evaluating 5 or 10 days of remdesivir treatment versus standard care in patients with moderate COVID-19 suggests there was clinical status improvement with the 5-day but not the 10-day remdesivir regimen versus standard care.14 In addition, there were no differences between the groups in other end points.
The results of this study are of questionable clinical significance, particularly given the similarities demonstrated in clinical status of 397 patients who received 5 versus 10 days of remdesivir.15 At the very least, the findings suggest that remdesivir should be reserved for patients with more severe disease. When the results of the ACTT-1 study were stratified based on severity, there was no difference between remdesivir and placebo groups in mild to moderate disease, but patients with severe disease had a median time to recovery of 12 days with remdesivir versus 18 days with placebo.6 Caution is needed when reporting results from a subgroup, but patients with severe disease may be the niche for whom remdesivir demonstrates the most benefit.
With other diseases, a reduced hospital length of stay may decrease 30-day readmission rates and mortality.16,17 Further study is needed to determine whether a decreased time to recovery reduces the length of stay in COVID-19. But if it does, potential benefits could include the reduced readmission rates or mortality benefits.
Conclusion
The FDA’s remdesivir EUA states that the drug is not recommended for patients with an eGFR of less than 30 mL/min unless the potential benefits outweigh the risk.8 The risk includes potential accumulation of the drug, it’s metabolite, or the solubility enhancing agent used with it, with unknown or theoretical AE potential as a result. The benefits include reduction of median time to recovery in hospitalized patients.6 This impact may be more profound in patients with severe disease.16 This benefit may or may not reduce the overall length of stay.
Ideally, as time passes and familiarity with remdesivir expands, case reports will emerge and clinical trials will be conducted in this patient population. Unfortunately, that does not help your patient today. Without utilization data from patients with acute or chronic kidney injury, remdesivir may not be considered, leaving this patient population without the opportunity to access a potentially beneficial treatment option.9
Weighing the risks and benefits, I believe the benefits of remdesivir will outweigh the risks for many of these patients. However, risk?benefit analysis needs to be performed for each patient. Although further study is needed, I think it is reasonable to consider not withholding remdesivir therapy based on a reduced eGFR or the use of hemodialysis alone.
References
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2. Luther MK, Timbrook TT, Caffrey AR, et al. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis. Crit Care Med. 2018;46(1):12-20.
3. Jorgensen SCJ, Kebriaei R, Dresser LD. Remdesivir: review of pharmacology, pre-clinical data, and emerging clinical experience for COVID-19. Pharmacotherapy. 2020;40(7):659-671.
4. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929-936.
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8. Gilead. Fact sheet for health care providers emergency use authorization (EUA) of Veklury (remdesivir). 2020. Revised August 2020. www.fda.gov/media/137566/download. Accessed September 2, 2020.
9. Adamsick ML, Gandhi RG, Bidell MR, et al. Remdesivir in patients with acute or chronic kidney disease and COVID-19. J Am Soc Nephrol. 2020;31(7):1384-1386.
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11. Luke DR, Tomaszewski K, Damle B, et al. Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD). J Pharm Sci. 2010;99(8):3291-3301.
12. Luke DR, Wood ND, Tomaszewski KE, et al. Pharmacokinetics of sulfobutylether-β-cyclodextrin (SBECD) in subjects on hemodialysis. Nephrol Dial Transplant. 2012;27(3):1207-1212.
13. von Mach MA, Burhenne J, Weilemann LS. Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy. BMC Clin Pharmacol. 2006;6:6. doi: 10.1186/1472-6904-6-6.
14. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020 Aug 21. [Epub ahead of print]. doi: 10.1001.jama.2020.16349.
15. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020 May 27. [Epub ahead of print]. doi: 10.1056/NEJMoa2015301.
16. Kaboli PJ, Go JT, Hockenberry J, et al. Associations between reduced hospital length of stay and 30-day readmission rate and mortality: 14-year experience in 129 Veterans Affairs hospitals. Ann Intern Med. 2012;157(12):837-845.
17. Lingsma H, Bottle A, Middleton S, et al. Evaluation of hospital outcomes: the relation between length-of-stay, readmission, and mortality in a large international administrative database. BMC Health Serv Res. 2018;18(1):116.
Dr. Peyko reported no relevant financial relationships.
