Treatment of Severe COVID-19 Infection With Remdesivir in Peritoneal Dialysis

Abstract

End-stage kidney disease (ESKD) has been shown to be correlated with an increased risk of COVID-19 infection and mortality. Remdesivir is an effective non-EUA U.S. Food and Drug Administration (FDA)-approved antiviral agent for the treatment of COVID-19 in hospitalized adult and pediatric patients, though a lack of data has prevented its use in patients with severe kidney disease including dialysis patients. Some observational studies report the use of remdesivir in hemodialysis patients, but there are no reports of patients treated with remdesivir on peritoneal dialysis. Dialysis modalities may affect drug pharmacokinetics, and safety and efficiency of remdesivir in peritoneal dialysis is unknown. We report the first case, to our knowledge, of using remdesivir in a patient treated with peritoneal dialysis with no significant adverse events. This case illustrates the potential for remdesivir to be considered in peritoneal dialysis patients with severe COVID infection. Proper risk analysis and careful monitoring should be done, given the unpredictable clearance of the drug.

Introduction

Patients with end-stage kidney disease (ESKD) are not only at an increased risk of contracting COVID-19 but also at risk for severe infection from COVID-19. Data from a large dialysis organization suggests approximately 5% of dialysis patients developed COVID-19 with approximately 25% mortality. ¹ Remdesivir, a widely used antiviral agent, has received authorization by the U.S. Food and Drug Administration (FDA) for the treatment of COVID-19 in adult and pediatric patients aged ≥28 days and weighing ≥3 kg with mild to moderate COVID-19 and are at high risk for progression to severe COVID-19 including hospitalization or death. ² Remdesivir has been associated with improved outcomes in patients with mild to severe COVID-19 without severe kidney disease.^3,4 Unfortunately, data regarding safety and efficacy of remdesivir in patients with severe kidney disease, including those on dialysis, is limited. Remdesivir prescribing information states that the “pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment” and that remdesivir “. . . is not recommended in patients with eGFR (glomerular filtration rate) less than 30 mL per minute.” ² Therein lies a critical gap in clinical knowledge regarding the utilization of remdesivir in an at-risk ESKD patient population which could benefit from remdesivir’s therapeutic affects in severe COVID-19 infection.

There are published observational studies of remdesivir treatment in patients with an eGFR less than 30 mL/min/1.73 m², as well as those with acute kidney injury complicating existing chronic kidney disease requiring hemodialysis (HD). ⁵ - ⁷ These reports have shown safety and tolerability of using remdesivir in patients with acute kidney injury and chronic kidney disease. The Canadian Treatments for COVID-19 (CATCO) conducted a randomized, open-label study comparing remdesivir to standard care over an 8-month period which did not exclude patients with impaired kidney function. The study demonstrated no increased risk of transaminitis or toxic kidney effects at day 5 in patients with impaired renal function including a few patients undergoing HD.^8,9 While published reports and ongoing studies include patients on HD, no data exist on patients treated with peritoneal dialysis (PD). Drug accumulation/removal in PD is very different than in HD. The net weekly clearance of most medications by PD is assumed to be similar to HD. However, the quantity of drug removed in PD depends on multiple characteristics including drug molecular weight, drug protein binding, drug volume of distribution, the type and duration of PD prescription, and residual renal function. ¹⁰ For example, a drug with high protein binding may be better cleared by PD through high protein losses in the effluent. We report the first case (to our knowledge) of use of remdesivir for severe COVID-19 infection in an ESKD patient treated with PD.

Case Report

The patient is a 74-year-old male with a notable history of insulin-dependent diabetes mellitus, renal cell carcinoma with nephrectomy, and ESKD on maintenance PD who presented to a large metropolitan medical center hospital admitted with COVID-19 infection confirmed by nasal swab PCR (^©2021 Cepheid Gene Xpert SARS-CoV-2/Flu/RSV). Chest X-ray imaging demonstrated multilobar infiltrates. The patient was transferred to the intensive care unit within 12 hours of presentation with escalation of oxygen requirement to 60 liters per minute by nasal canula to maintain oxygen saturations greater than 89%. Chemistries were also notable for worsening hyperglycemia, anion gap metabolic acidosis, and elevated b-hydroxybutyrate, consistent with diabetic ketoacidosis. Patient was started on ceftriaxone and azithromycin for empiric coverage of community-acquired pneumonia, and dexamethasone for COVID-19 pneumonia. The suitability of remdesivir treatment for the patient’s concomitant severe COVID-19 infection with specific regard to safety and monitoring was considered by the critical care, renal, and pharmacy teams. The concomitant metabolic derangements in this patient further heightened the medical team’s concern for patient safety. After a discussion of the benefits versus risks of remdesivir with the patient, he agreed to proceed with remdesivir treatment, given the severity of his COVID-19 infection. The critical care, renal, and pharmacy teams opted to monitor daily renal clearance and liver function while dosing remdesivir daily for 5 days total. Remdesivir would be discontinued if liver enzymes increased to greater than 5 times the upper limit of normal. The patient continued to receive daily PD and treatment for diabetic ketoacidosis with intravenous insulin and normal saline hydration.

Six-Day Clinical Course (Tables 1-3)

Patient was started on dexamethasone, remdesivir, and consented to receive an experimental research drug (ACTIV-3: Therapeutics for Inpatients With COVID-19 [TICO]) ¹¹ while receiving daily PD. Peritoneal culture and cell counts were obtained through PD effluent sampling on day 1 in the intensive care unit and were unrevealing for bacterial peritonitis. Patient was a rapid/fast transporter on prior outpatient PD equilibration testing. After an initial trial of lower dwell volume to ensure tolerance, exchanges were increased to 6 cycles of 2 liters from 5 cycles (home regimen) to improve metabolic clearance, with a weekly kt/v of 2.2 (Fadem PD kt/V calculator) excluding residual renal function (minimal urine output). Dialysate dextrose concentration was initially 1.5% in context of diabetic ketoacidosis, subsequently adjusted daily to achieve and maintain euvolemia. The patient’s respiratory status improved to achieve SpO₂ of 95% on 8 liters nasal canula by the fifth dose of remdesivir (Table 1). His metabolic derangements also normalized with resolution of his metabolic acidosis and normalization of his anion gap (Table 2). While there was a trending rise in liver function tests, this was insignificant and remained within the normal range. In addition, there was no clinical evidence for acute liver dysfunction. The patient was transferred out of the intensive care on day 6 to a step-down unit where he continued to improve in respiratory status and correction of metabolic derangements.

Table 1.

Vital Signs Trend.

Vitals	Initial	Day 1 ICU* (remdesivir)	Day 2	Day 3	Day 4	Day 5
Temperature (°C)	38.1	35.8	36.7	36.6	36.4	36.7
Pulse (beats/min)	108	85	78	93	81	73
Respiratory rate (breaths/min)	30	28	23	24	18	25
O2 saturation (%) a	83	95	97	92	94	92
Blood pressure (mm Hg)	153/74	101/58	102/58	112/99	128/56	124/70

*ICU, Intensive Care Unit.

a

Patient required supplemental oxygenation.

Table 2.

Chemistry Panel Trend.

Chemistries	Initial	Day 1 ICU* (remdesivir)	Day 2	Day 3	Day 4	Day 5
Na (mmol/liter)	135	139	140	139	141	143
K (mmol/liter)	5.9	4.2	3.8	4.3	3.6	3.9
Cl− (mmol/liter)	108	103	102	101	96	98
HCO3 (mmol/liter)	11	13	15	16	20	22
BUN (mg/dL)	88	98	86	93	90	84
Cr (mg/dL)	11.02	11.61	10.88	10.87	9.48	9.87
ALT (IU/L)	16	16	16	18	20	27
AST (IU/L)	9	17	16	18	24	34
Prothrombin time (seconds)	14.2	14.6	15.1
Partial thromboplastin time (seconds)		39.3	38

*

ICU, Intensive Care Unit.

Table 3.

Hematology Profile Trend.

Hematology profile	Initial	Day 1 ICU* (remdesivir)	Day 2	Day 3	Day 4	Day 5
Hemoglobin (g/dL)	11.8	11.6	10.4	9.4	10	10.7
Hematocrit (%)	35.3	35.1	30.3	28.5	29.6	31.8
White blood count (×103/µL)	11.0	11.4	14.7	11.9	12.5	13.2
Platelets (×103/µL)	215	205	276	267	236	264

*

ICU, Intensive Care Unit.

Discussion

This case illustrates the safe therapeutic usage of remdesivir in a case of severe COVID-19 infection complicated by metabolic derangement in a patient on chronic PD. While literature has demonstrated that remdesivir can be safely used in patients on chronic HD, to our knowledge, this is the first reported case of using remdesivir in chronic PD with good efficacy in treating hypoxemic respiratory failure. The most common side effects associated with remdesivir include increases in serum glucose levels and increases/decreases in creatinine clearance. Side effects occurring in less than 10% of reports include skin rash, nausea, decreased hemoglobin, lymphocytopenia, prolonged prothrombin time, increased serum alanine aminotransferase and aspartate aminotransferase, hypersensitivity reaction, and seizure. Remdesivir has been associated with bradycardia (including severe bradycardia and sinus bradycardia), heart failure, hypotension, acute hepatic failure, hepatitis, and anaphylaxis in postmarketing reports. ¹² In addition, remdesivir is solubilized by the carrier molecule sodium sulfobutylether-beta (β)-cyclodextran (SBECD), a large (>2000 g/mol) cyclical compound with a molecular weight of approximately 2163.^13,14 The average maximum threshold for safety of SBECD in a 70-kg patient is 17.5 g (250 mg/kg per day); remdesivir 100 mg solution and lyophilized powder contains 6 g and 3 g of SBECD, respectively.^2,6 Sulfobutylether-beta (β)-cyclodextran accumulates in the setting of renal dysfunction and could lead to liver necrosis. It is known to be well-cleared by HD (46% removed by an approximate 4-hour dialysis session).^2,13,14 Sulfobutylether-beta (β)-cyclodextran is also effectively removed by continuous venovenous hemofiltration without significant accumulation. ¹⁵ The penetrance of SBECD to peritoneal fluid is unknown, although given the known clearance of complex, large molecular weight molecules (such as dextrans of molecular weight up to 150 000 g/mol) to PD effluent, it is likely there is some clearance. ¹⁶ Sulfobutylether-beta (β)-cyclodextran is also a carrier in voriconazole solution for injection, where there are 16 mg of SBECD per 1 mg of voriconazole; thus for a 70-kg patient receiving voriconazole 4 mg/kg IV every 12 hours, the daily SBECD dose would be 8.96 g or 128 mg/kg per day.^17,18 A systematic review of IV voriconazole use in patients with baseline renal impairment evaluated 7 retrospective studies and concluded that there was no evidence that the use of intravenous voriconazole increased incidence of worsening renal function. ¹⁸ Although SBECD exposure is higher than in patients with normal kidney function, renal replacement therapy 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. Pharmacokinetic profile of SBECD has been demonstrated a low volume of distribution and a short half-life. ¹⁴ In healthy volunteers who received SBECD 100 mg/kg twice on day 1, then 50 mg/kg twice daily for days 2 to 10, the day 1 half-life and volume of distribution at steady state was 1.4 hours and 185 ± 19 mL/kg respectively, and at day 10 was 1.6 hours and 208 ± 19 mL/kg, respectively. ¹⁴ Given these parameters, administration of drugs (and associated drug vehicles) with potentially high or unknown toxicities, within the context of limited ESKD-specific pharmacokinetic data, requires careful patient monitoring. The interdisciplinary team was aware of side effects of SBECD accumulation; however, due to the lower daily dose of SBECD from remdesivir (as compared to SBECD doses seen with intravenous voriconazole), ¹⁸ potential for partial clearance with daily PD, and the limited 5-day treatment duration of the planned remdesivir course, it was recommended to the patient he receive all available treatment options for severe COVID-19 infection, including remdesivir. In conclusion, we recommend remdesivir should be considered in PD patients with severe COVID infection in conjunction with a detailed risk/benefit analysis, given the unpredictable drug clearance, informed consent of the patient or surrogate decision maker, and close monitoring of clinical/laboratory data.