key: cord-0763232-ejezwff1
authors: Biever, Paul; Staudacher, Dawid L.; Sommer, Michaela J.; Triebel, Hannah; Neukamm, Merja A.; Bode, Christoph; Supady, Alexander; Lother, Achim
title: Hemoadsorption eliminates remdesivir from the circulation: Implications for the treatment of COVID‐19
date: 2021-03-12
journal: Pharmacol Res Perspect
DOI: 10.1002/prp2.743
sha: 331afc48a3e70f3c4859a6e45a9067fbebf1606c
doc_id: 763232
cord_uid: ejezwff1

Both antiviral treatment with remdesivir and hemoadsorption using a CytoSorb(®) adsorption device are applied in the treatment of severe COVID‐19. The CytoSorb(®) adsorber consists of porous polymer beads that adsorb a broad range of molecules, including cytokines but also several therapeutic drugs. In this study, we evaluated whether remdesivir and its main active metabolite GS‐441524 would be adsorbed by CytoSorb(®). Serum containing remdesivir or GS‐441524 was circulated in a custom‐made system containing a CytoSorb(®) device. Concentrations of remdesivir and GS‐441524 before and after the adsorber were analyzed by liquid chromatography‐tandem mass spectrometry. Measurements of remdesivir in the outgoing tube after the adsorber indicated almost complete removal of remdesivir by the device. In the reservoir, concentration of remdesivir showed an exponential decay and was not longer detectable after 60 mins. GS‐441524 showed a similar exponential decay but, unlike remdesivir, it reached an adsorption–desorption equilibrium at ~48 µg/L. Remdesivir and its main active metabolite GS‐441524 are rapidly eliminated from the perfusate by the CytoSorb(®) adsorber device in vitro. This should be considered in patients for whom both therapies are indicated, and simultaneous application should be avoided. In general, plasma levels of therapeutic drugs should be closely monitored under concurrent CytoSorb(®) therapy.

In humans, infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 , which can lead, in severe cases, to excessive inflammation and ultimately to life-threatening pneumonia. Antiviral treatment with remdesivir, a nucleoside analogue hampering the viral RNA polymerase, was recommended for hospitalized patients with severe COVID-19. 1, 2 Beyond this, extracorporeal cytokine adsorption using a CytoSorb ® adsorption device (CytoSorbents Corp., Monmouth Junction, New Jersey, USA) was suggested for mitigation of excessive inflammatory response in COVID-19. 3 The CytoSorb ® adsorber consists of porous polymer beads that adsorb molecules within the 5-55 kDa range, including cytokines, myoglobin, or bilirubin, but also therapeutic drugs. 4 It can be integrated in extracorporeal membrane oxygenation systems or continuous renal replacement therapy circuits and is used for different indications, including intoxications, rhabdomyolysis, liver failure, or septic shock. 4 Recently, the United States Food and Drug Administration has authorized the emergency use of the CytoSorb ® adsorber for the treatment of COVID-19 5 but there are no data available on potential interaction with remdesivir use. Thus, the aim of this study was to investigate whether remdesivir would be adsorbed by CytoSorb ® .

Remdesivir is a prodrug that is rapidly metabolized in humans to its main active metabolite GS-441524. 6 To evaluate the capacity of the CytoSorb ® hemoadsorption device to eliminate remdesivir or GS-441524, we applied a previously published protocol. 7,8 A CytoSorb ® device was integrated in a custom-made system using a peristaltic pump (AlphaControl PSP-V12G, Figure 1 ) and primed with fetal calf serum (Sigma-Aldrich, Taufkirchen, Germany).

Remdesivir (1200 µg/L) or GS-441524 (200 µg/L, both Cayman Chemical, Ann Arbor, MI, USA) at concentrations similar to plasma levels observed in humans 6 was dissolved in 2,000 mL serum supplemented with NaF (2.5 g/L) for stabilization. The solutions were circulated from a reservoir at a flow rate of 200 mL/ min for 60 mins at 36.5°C in two separate experiments. Samples (1 mL) were taken from the circuit simultaneously before (pre) and after (post) the adsorption device at 0, 5, 10, 15, 30, and 60 mins ( Figure 1 ). The adsorption device was replaced after each experiment. Concentrations of remdesivir (linearity 25-1000 ng/mL, limit of detection 0.54 ng/mL, limit of quantification 1.1 ng/mL) and GS-441524 (linearity 2.5-100 ng/mL, limit of detection 0.82 ng/mL, limit of quantification 0.84 ng/mL) were analyzed within 4 h by F I G U R E 1 Experimental setup. A CytoSorb ® device was integrated in a custom-made system, and serum containing remdesivir or GS-441524, respectively, was circulated from a reservoir at a flow rate of 200 mL/min. Samples were taken from the circuit before (pre) and after (post) the adsorber device at 0, 5, 10, 15, 30, and 60 minutes for quantification of remdesivir or GS-441524

Concentrations of remdesivir or GS-441524 in samples taken from the circuit before (pre) and after (post) the adsorber device were quantified by liquid chromatography with mass spectrometry detection. Dashed lines indicate calculated half-life (t 1/2 ) a liquid chromatography-tandem mass spectrometry method after protein precipitation using D4-remdesivir as internal standard (modified after 9 ). Half-lives were calculated by a one-phase exponential decay model (Y = (Y0-NS)*exp(−K*X) + NS) using GraphPad Prism 9.0.0. 

Our results show that remdesivir and GS-441524 are rapidly elimi- this time. 1, 2 In contrast, hemoadsorption therapy may be limited to critical cases of COVID-19 that are associated with a significant increase in cytokine levels. This, however, remains to be confirmed. 3

demand careful consideration. This is particularly true for antiviral drugs, for which significant drug-drug interactions have been described, 11 but also includes non-pharmacological therapies. Our data suggest that concurrent use of remdesivir and hemoadsorption should rather be avoided and support the view that sequential use at different stages of COVID-19 may be preferred. The results

presented here complement previous reports describing desired or unwanted adsorption of various molecules by the CytoSorb ® device. 7, 8, [12] [13] [14] [15] In vitro data are available on a broad range of therapeutic drugs that are commonly used in intensive care medicine ( 

None. 

The authors confirm that the data supporting the findings of this study are available within the article.

Not applicable.

Achim Lother https://orcid.org/0000-0001-9107-5558

National Institutes of Health COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation

Hemoadsorption with CytoSorb ®

United States Food and Drug Administration: CytoSorb ® Emergency Use Authorization for Use in Patients with COVID-19 Infection

Safety, tolerability, and pharmacokinetics of remdesivir, an antiviral for treatment of COVID-19, in healthy subjects

Use of the CytoSorb adsorption device in MDMA intoxication: a first-in-man application and in vitro study

In vitro removal of therapeutic drugs with a novel adsorbent system

Quantification of plasma remdesivir and its metabolite GS-441524 using liquid chromatography coupled to tandem mass spectrometry. Application to a Covid-19 treated patient

Remdesivir inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice

Drug-drug interactions with candidate medications used for COVID-19 treatment: an overview

Removal of dabigatran using sorbent hemadsorption

In-Vitro sorbent-mediated removal of edoxaban from human plasma and albumin solution

Extracorporeal hemoperfusion as a potential therapeutic option for critical accumulation of rivaroxaban

Ticagrelor removal from human blood

Hemoadsorption eliminates remdesivir from the circulation: Implications for the treatment of COVID-19