How to use COVID-19 antiviral drugs in patients with chronic kidney disease

The COVID-19 pandemic, caused by SARS-CoV-2, disproportionately affects patients with comorbidities, particularly those with chronic kidney disease (CKD). CKD increases susceptibility to severe COVID-19 due to secondary immunodeficiency, leading to higher hospitalization and mortality rates. The challenge lies in selecting appropriate therapies for COVID-19 patients with impaired kidney function, as many clinical studies exclude this population, limiting readily available pharmacokinetic and pharmacodynamic data. Current COVID-19 treatment options include vaccination, anti-inflammatory agents, anticoagulants, monoclonal antibodies, and antiviral therapies. However, the use of antivirals like Remdesivir, Nirmatrelvir/Ritonavir, Azvudine, and Molnupiravir in CKD patients requires careful consideration due to potential nephrotoxicity and altered drug metabolism. Other drugs with potential antiviral activity against SARS-CoV-2 include Atazanavir, Oseltamivir, Famciclovir, Darunavir, Sofosbuvir, Favipiravir, Ribavirin, and Umifenovir. These drugs also present challenges in CKD patients due to their renal elimination and potential for drug interactions. This review aims to address the knowledge gap regarding the safe and effective use of these antiviral drugs and monoclonal antibodies in treating COVID-19 patients with CKD.

The authors conducted a comprehensive literature review using various databases (ClinicalTrials.gov, FDA, WHO, CDC, PubMed, IDSA, Web of Science, ScienceDirect) and official websites, analyzing clinical trials, clinical reports, guidelines, and reviews published between 1993 and 2022. The review focused on English-language articles examining the demographic data and clinical outcomes related to the use of antiviral drugs in COVID-19 patients with CKD. The review covers the pharmacokinetic and pharmacodynamic properties of several antiviral drug classes (RdRp inhibitors, protease inhibitors, neuraminidase inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide polymerase inhibitors, and fusion inhibitors) and monoclonal antibodies, focusing on their renal clearance, metabolism, potential for nephrotoxicity, and dosage adjustments in patients with varying stages of CKD. The review highlights the scarcity of data on these drugs' use in CKD patients with COVID-19 and the need for more studies.

The authors reviewed existing literature on the pharmacokinetic and pharmacodynamic properties of several antiviral drugs and monoclonal antibodies used in COVID-19 treatment. This included examining their mechanism of action, absorption, distribution, metabolism, excretion (ADME), and renal clearance. The studies reviewed included clinical trials, case reports, and official guidelines from various international and national health agencies. The data was analyzed to assess the safety, efficacy, dosage, and frequency of administration of each drug in patients with different stages of CKD. The analysis considered the potential for drug interactions, nephrotoxicity, and other adverse effects. The study also examined how factors like glomerular filtration rate (GFR), creatinine clearance, and dialysis affected drug pharmacokinetics. Each drug was reviewed individually for its mechanism, pharmacokinetic profile, rationale for use in COVID-19, limitations, and adverse effects in CKD patients. This information was then compiled into tables summarizing the safety profile and recommended dosage adjustments based on CKD stage.

The review found significant variations in the safety and efficacy of different antiviral drugs and monoclonal antibodies in COVID-19 patients with CKD. **Remdesivir:** While effective against SARS-CoV-2, its renal excretion and use of sulfobutylether-β-cyclodextrin as a carrier for intravenous injection raise concerns about nephrotoxicity in advanced CKD stages. Nasal administration may mitigate this risk. **Molnupiravir:** Its active metabolite is not significantly renally eliminated, making it suitable for CKD patients without dose adjustments. However, it is contraindicated in pregnant women, individuals under 18, and the elderly. **Famciclovir:** Its renal elimination necessitates dose adjustments in CKD patients based on creatinine clearance. **Ribavirin:** Primarily renally excreted, dose reductions are needed in patients with impaired kidney function, and monitoring of hematological parameters is crucial due to its potential for anemia. It’s contraindicated in pregnant and breastfeeding women. **Favipiravir:** Predominantly renally excreted, its use is cautioned in CKD due to potential accumulation of a metabolite (M1) leading to increased uric acid levels and possible nephrotoxicity. **Atazanavir:** Primarily eliminated through the biliary route, dose adjustments are generally not necessary in CKD, but caution is warranted in severe CKD. **Darunavir:** Low renal clearance and high protein binding mean dose adjustments are usually unnecessary in CKD. However, there are case reports of AKI. **Nirmatrelvir/Ritonavir:** Dose adjustments are necessary in patients with mild to moderate CKD. Not recommended in severe kidney disease. **Lopinavir/Ritonavir:** Prolonged use can cause kidney injury. Not recommended for CKD patients. **Oseltamivir:** The active metabolite shows minimal changes in pharmacokinetics with severe kidney impairment; therefore, low-dose administration may be considered in CKD patients, although efficacy needs further investigation. **Azvudine:** While showing promise and limited evidence of renal adverse events, more data are needed, especially in severe CKD. **Dolutegravir/Rilpivirine:** Minimal renal excretion suggests minimal need for dose adjustments in CKD patients. **Sofosbuvir:** Primarily cleared by kidneys, dose reductions are needed for patients with creatinine clearance below 30 ml/min. It may cause AKI. **Umifenovir:** Associated with increased in-hospital mortality and acute kidney injury in patients with severe COVID-19, particularly those with renal insufficiency; it is therefore not suitable for CKD patients. **Monoclonal Antibodies:** Several monoclonal antibody combinations (Bamlanivimab/Etesevimab, Casirivimab/Imdevimab, Sotrovimab, Tocilizumab, Adalimumab, Sarilumab) generally do not require dose adjustments in CKD patients but may present other challenges in severe cases.

The findings highlight the complex interplay between antiviral drug pharmacokinetics, CKD severity, and COVID-19 outcomes. The significant variability in renal clearance and potential for nephrotoxicity among the reviewed drugs underscores the need for individualized treatment plans based on patients' GFR and other clinical factors. Many clinical trials exclude patients with CKD, leaving a significant knowledge gap regarding optimal treatment strategies. The information provided in this review can assist clinicians in making informed decisions about antiviral drug selection for COVID-19 patients with CKD, The relatively safe drugs like Molnupiravir, Azvudine, and Dolutegravir, which are not significantly cleared by the kidneys, present promising options. While monoclonal antibodies present less nephrotoxic potential, further investigation into their use is needed for hospitalized or severely ill COVID-19 patients.

This review provides a valuable resource for clinicians managing COVID-19 in patients with CKD by summarizing available data on the safety and efficacy of various antiviral drugs and monoclonal antibodies. However, the authors stress that these recommendations are based on currently available data, and larger, well-designed clinical trials specifically in CKD populations are needed to establish more definitive dosing guidelines and safety profiles. Future research should focus on the comparative effectiveness and safety of different treatment regimens, considering the potential for drug interactions and the evolving landscape of SARS-CoV-2 variants. The information will help guide the selection of appropriate therapies for COVID-19 patients with CKD while motivating further research in this area.

The review's conclusions are limited by the available evidence, which is often sparse for CKD populations. The studies reviewed varied in methodology, sample size, and patient characteristics, limiting the generalizability of some findings. The review primarily focused on English-language publications, potentially excluding relevant research from other languages. Furthermore, the rapidly evolving nature of SARS-CoV-2 variants and the emergence of new treatments may necessitate ongoing updates to the recommendations.