Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database

Abstract: BRIEF REPORT Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database Alexandre O. Gérard1,2, Audrey Laurain1, Audrey Fresse2, Nadège Parassol2, Marine Muzzone2, Fanny Rocher2, Vincent L.M. Esnault1 and Milou-Daniel Drici2,* Remdesivir is approved for emergency use by the US Food and Drug Administration (FDA) and authorized conditionally by the European Medicines Agency (EMA) for patients with coronavirus disease 2019 (COVID-19). Its benefit-risk ratio is still being explored because data in the field are rather scant. A decrease of the creatinine clearance associated with remdesivir has been inconstantly reported in clinical trials with unclear relevance. Despite these uncertainties, we searched for a potential signal of acute renal failure (ARF) in pharmacovigilance postmarketing data. An analysis of the international pharmacovigilance postmarketing databases (VigiBase) of the World Health Organization (WHO) was performed, using two disproportionality methods. Reporting odds ratio (ROR) compared the number of ARF cases reported with remdesivir, with those reported with other drugs prescribed in comparable situations of COVID-19 (hydroxychloroquine, tocilizumab, and lopinavir/ritonavir). The combination of the terms “acute renal failure” and “remdesivir” yielded a statistically significant disproportionality signal with 138 observed cases instead of the 9 expected. ROR of ARF with remdesivir was 20-fold (20.3; confidence interval 0.95 [15.7–26.3], P < 0.0001]) that of comparative drugs. Based on ARF cases reported in VigiBase, and despite the caveats inherent to COVID-19 circumstances, we detected a statistically significant pharmacovigilance signal of nephrotoxicity associated with remdesivir, deserving a thorough qualitative assessment of all available data. Meanwhile, as recommended in its Summary of Product Characteristics, assessment of patients with COVID-19 renal function should prevail before and during treatment with remdesivir in COVID-19. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?  Remdesivir is a nucleoside analog recently approved by the US Food and Drug Administration (FDA) for emergency use and conditionally authorized by the European Medicines Agency (EMA) in patients with coronavirus disease 2019 (COVID-19), although data pertaining to its effectiveness and safety are scant. A decrease of the creatinine clearance has been reported inconstantly in clinical trials. WHAT QUESTION DID THIS STUDY ADDRESS?  Is there a potential signal of a risk of acute renal failure associated with remdesivir in pharmacovigilance postmarketing databases? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?  There is a statistically suggestive disproportionality signal regarding the association of acute renal failure and remdesivir. This possible signal stood out when calculating the reporting odds ratio compared with 3 drugs used in patients with COVID-19. However, many confounding factors persist. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?  These results raise awareness about a possible pharmacovigilance signal regarding the risk of acute renal failure associated with remdesivir, currently being qualitatively explored by regulatory agencies. Meanwhile, close serum creatinine monitoring seems warranted in patients treated with remdesivir. Remdesivir is an antiviral prodrug belonging to the adenosine nucleoside analog family, which is..