.jpg "Danielle Green, MD photo")
Carina Imburgia, BS
Laboratory Specialist
Department of Pediatrics, University of Utah, United States
Disclosure information not submitted.
Joseph Rower, PhD, DABCP
Research Assistant Professor
Department of Pharmacology and Toxicology; Associate Director, Center for Human Toxicology, University of Utah, United States
Disclosure information not submitted.
Autumn McKnite, BS
Research Assistant
Depatment of Pharmacology and Toxicology, United States
Disclosure information not submitted.
Walter Kelley, DO, FCAP
Medical Director
American Red Cross; Assistant Professor of Pathology, University of Arizona College of Medicine - Tucson, United States
Disclosure information not submitted.
Christopher Reilly, PhD
Professor of Pharmacology and Toxicology
Director, Center for Human Toxicology, University of Utah, United States
Disclosure information not submitted.
Kevin Watt, MD, PhD
Chief, Division of Pediatric Clinical Pharmacology; Associate Professor of Pediatrics
Division of Pediatric Critical Care Medicine, University of Utah, United States
Disclosure information not submitted.
Title: Remdesivir Extraction by Extracorporeal Life Support Circuits
Introduction: Many patients with severe COVID-19 require extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapy (CRRT), both of which can alter drug disposition. Lipophilic, highly protein bound drugs can adsorb to circuit materials, while hydrophilic, minimally protein bound drugs are likely to be filtered.
Hypothesis: Remdesivir (RDV) is lipophilic and highly protein bound making it likely to be adsorbed by circuit components and minimally cleared by hemofiltration/dialysis. RDV’s active metabolite GS-441524 is hydrophilic and minimally protein bound and should be minimally adsorbed but rapidly filtered.
Methods: We administered RDV and GS-441524 to blood-primed, closed loop, ex vivo ECMO and CRRT circuits and measured drug concentrations over time. Drugs were also administered to a separate control tube to determine drug degradation. Each experiment was performed in triplicate. Drug recovery (%) was calculated by dividing each concentration by the initial concentration.
Results: Mean (standard deviation) recovery of RDV in the ECMO circuits (n=3) was low at 33.3% (2.0) at 6 hours. Recovery in the control (n=3) at 6 hours was 29.3% (2.0) and not significantly different from recovery in the ECMO circuits at 6 hours (p=0.07). Substantial loss of RDV in the CRRT circuits (n=3) occurred within minutes. Recovery was 14.4% (5.7) at 5 minutes and 4.7% (1.0) at 3 hours and significantly different compared to control recovery at 3 hours (p=0.008).
Recovery of GS-441524 was higher than RDV in the ECMO circuits (n=3). After 6 hours, recovery was at 75.8% (16.5). Mean recovery in the control (n=3) at 6 hours was 70.6% (6.2) and not significantly different from recovery in the ECMO circuit at 6 hours (p=0.7). In the CRRT circuits (n=3), GS-441524 recovery was low at 15.9% (3.0) at 30 minutes and 0% (0) at 3 hours and significantly different from the control (p=0.005).
Conclusions: RDV is extracted by ECMO and CRRT primarily by drug adsorption to circuit materials and potentially by drug metabolism in the blood. GS-441524 was not substantially extracted by the ECMO circuit but rapidly cleared by hemodiafiltration in the CRRT circuit. The extent of loss for both molecules, especially in CRRT, suggests that in patients supported with ECMO and CRRT, dosing adjustments are needed.