Remdesivir and GS-441524 Extraction by Ex Vivo Extracorporeal Life Support Circuits

Patients with severe, COVID-related multi-organ failure often require extracorporeal life support (ECLS) such as extracorporeal membrane oxygenation (ECMO) or continuous renal replacement therapy (CRRT). An ECLS can alter drug exposure via multiple mechanisms. Remdesivir (RDV) and its active metabolite GS-441524 are likely to interact with ECLS circuits, resulting in lower than expected exposures. We evaluated circuit-drug interactions in closed loop, ex vivo ECMO and CRRT circuits. We found that mean (standard deviation) recovery of RDV at 6 hours after dosing was low in both the ECMO (33.3% [2.0]) and CRRT (3.5% [0.4]) circuits. This drug loss appears to be due primarily to drug adsorption by the circuit materials and potentially due to metabolism in the blood. GS-441524 recovery at 6 hours was high in the ECMO circuit 75.8% (16.5); however, was not detectable at 6 hours in the CRRT circuit. Loss in the CRRT circuit appears to be due primarily to efficient hemodiafiltration. The extent of loss for both molecules, especially in CRRT, suggests that in patients supported with ECMO and CRRT, RDV dosing adjustments are needed.