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

Abstract

Antiviral drugs such as Remdesivir (Veklury), Nirmatrelvir with Ritonavir (Paxlovid), Azvudine, and Molnupiravir (Lagevrio) can reduce the risk for severe and fatal Coronavirus Disease (COVID)-19. Although chronic kidney disease is a highly prevalent risk factor for severe and fatal COVID-19, most clinical trials with these drugs excluded patients with impaired kidney function. Advanced CKD is associated with a state of secondary immunodeficiency (SIDKD), which increases the susceptibility to severe COVID-19, COVID-19 complications, and the risk of hospitalization and mortality among COVID-19 patients. The risk to develop COVID-19 related acute kidney injury is higher in patients with precedent CKD. Selecting appropriate therapies for COVID-19 patients with impaired kidney function is a challenge for healthcare professionals. Here, we discuss the pharmacokinetics and pharmacodynamics of COVID-19-related antiviral drugs with a focus on their potential use and dosing in COVID-19 patients with different stages of CKD. Additionally, we describe the adverse effects and precautions to be taken into account when using these antivirals in COVID-19 patients with CKD. Lastly, we also discuss about the use of monoclonal antibodies in COVID-19 patients with kidney disease and related complications.

Keywords: COVID-19; antivirals; chronic kidney disease; clinical trials; monoclonal antibodies; pharmacodynamics; pharmacokinetics.

FIGURE 1

Chemical structure of (A) Remdesivir, (B) Atazanavir, (C) Molnupiravir, (D) Oseltamivir, (E) Azvudine, (F) Famciclovir, (G) Darunavir, (H) Dolutegravir.

FIGURE 2

Chemical structure of (A) Rilpivirine, (B) Sofosbuvir, (C) Nirmatrelvir, (D) Ritonavir, (E) Favipiravir, (F) Ribavirin, (G) Umifenovir, (H) Lopinavir.

FIGURE 3

An overview of SARS-CoV-2’s life cycle along with the potential targets of anti-viral drugs and monoclonal antibodies in COVID-19. On host cells, the spike protein (S) of SARS-CoV-2 interacts with the cellular receptor ACE2 followed by viral entry into the host cell. It happens either by fusion of the virus with plasma membrane due to activation by serine protease or activation by endocytic machinery of the host resulting in viral and cellular membranes fusion. The viral genome is unveiled in the cytoplasm and translated to viral replicase polyproteins (PP1a and PP1ab) followed by subsequent cleavage to form nonstructural proteins (nsps) via proteinases of the virus. Some of the nsps consequently form the replicase-transcriptase complex as RNA-dependent RNA polymerase (RdRp). Through intermittent transcription, the polymerase generates subgenomic mRNA series that is ultimately translated into functional viral proteins. In the cytoplasm, viral nucleocapsids are formed with genomic RNA and N proteins accompanied by budding in the ERGIC lumen. The virus is then released from the host’s infected cell to the extracellular space via exocytosis. Medications with significant anti-SARS-CoV-2 action including anti-viral drugs and monoclonal antibodies acting on the different phases of the virus’s life cycle have been also illustrated in the figure. Abbreviation- S: Structural proteins, E: Envelope, M: Membrane, N: Nucleocapsid, ACE2: Angiotensin-converting enzyme 2, ERGIC: Endoplasmic Reticulum- Golgi intermediate compartment.