Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19

doi:10.1128/AAC.01521-20

. 2020 Oct 20;64(11):e01521-20.

doi: 10.1128/AAC.01521-20. Print 2020 Oct 20.

Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19

Minh Patrick Lê^{1

2}, Quentin Le Hingrat^{3

4}, Pierre Jaquet⁵, Paul-Henri Wicky⁵, Vincent Bunel⁶, Laurent Massias^{7

4}, Benoit Visseaux^{3

4}, Jonathan Messika⁶, Diane Descamps^{3

4}, Hervé Mal⁶, Jean-François Timsit^{4

5}, Gilles Peytavin^{7

4}

Affiliations

¹ AP-HP, Bichat Claude Bernard Hospital, Pharmacology-Toxicology Department, Paris, France minh.le@aphp.fr.
² INSERM, UMRS 1144, Université de Paris, Paris, France.
³ AP-HP, Bichat Claude Bernard Hospital, Virology Department, Paris, France.
⁴ IAME, INSERM, UMRS 1137, Université de Paris, Paris, France.
⁵ AP-HP, Bichat Claude Bernard Hospital, Medical and Infectious Diseases ICU (MI2), Paris, France.
⁶ AP-HP, Bichat Claude Bernard Hospital, Pneumology B and Lung Transplant Department, INSERM 1152, Paris, France.
⁷ AP-HP, Bichat Claude Bernard Hospital, Pharmacology-Toxicology Department, Paris, France.

PMID: 32868327
PMCID: PMC7577145
DOI: 10.1128/AAC.01521-20

Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19

Minh Patrick Lê et al. Antimicrob Agents Chemother. 2020.

. 2020 Oct 20;64(11):e01521-20.

doi: 10.1128/AAC.01521-20. Print 2020 Oct 20.

Authors

Affiliations

¹ AP-HP, Bichat Claude Bernard Hospital, Pharmacology-Toxicology Department, Paris, France minh.le@aphp.fr.
² INSERM, UMRS 1144, Université de Paris, Paris, France.
³ AP-HP, Bichat Claude Bernard Hospital, Virology Department, Paris, France.
⁴ IAME, INSERM, UMRS 1137, Université de Paris, Paris, France.
⁵ AP-HP, Bichat Claude Bernard Hospital, Medical and Infectious Diseases ICU (MI2), Paris, France.
⁶ AP-HP, Bichat Claude Bernard Hospital, Pneumology B and Lung Transplant Department, INSERM 1152, Paris, France.
⁷ AP-HP, Bichat Claude Bernard Hospital, Pharmacology-Toxicology Department, Paris, France.

PMID: 32868327
PMCID: PMC7577145
DOI: 10.1128/AAC.01521-20

Abstract

Remdesivir has reported efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in vivo Drug-drug interactions limit therapeutic options in transplant patients. Remdesivir and its metabolite GS-441524 are excreted principally in urine. In intensive care unit (ICU) settings, in which multiple-organ dysfunctions can occur rapidly, hemodialysis may be a viable option for maintaining remdesivir treatment, while improving tolerance, by removing both remdesivir's metabolite (GS-441524) and sulfobutylether β-cyclodextrin sodium (SEBCD). Additional studies may prove informative, particularly in the evaluations of therapeutic options for coronavirus disease 2019 (COVID-19).

Keywords: hemodialysis; pharmacokinetics; remdesivir.

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Figures

**FIG 1**
Timeline of the clinical endpoints, immunomodulation therapy, and antimicrobial chemotherapy for our patient. AMC, amoxicillin-clavulanic acid; CS, corticosteroid pulses; DXM, dexamethasone; ISA, isavuconazole; MPA, mycophenolate; RDV, remdesivir; SXT, sulfamethoxazole-trimethoprim; TZP, piperacillin-tazobactam; VAL, valganciclovir.

**FIG 2**
Biotransformation of remdesivir (inactive prodrug) into GS-441524 and then GS-443902 (active metabolite, triphosphate analogue).

See this image and copyright information in PMC

Comment in

Reply to Yan and Muller, "Captisol and GS-704277, but Not GS-441524, Are Credible Mediators of Remdesivir's Nephrotoxicity".
Lê MP, Le Beller C, Le Hingrat Q, Jaquet P, Wicky PH, Bunel V, Massias L, Visseaux B, Messika J, Descamps D, Mal H, Timsit JF, Peytavin G. Lê MP, et al. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01937-20. doi: 10.1128/AAC.01937-20. Print 2020 Nov 17. Antimicrob Agents Chemother. 2020. PMID: 32988815 Free PMC article. No abstract available.
Captisol and GS-704277, but Not GS-441524, Are Credible Mediators of Remdesivir's Nephrotoxicity.
Yan VC, Muller FL. Yan VC, et al. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01920-20. doi: 10.1128/AAC.01920-20. Print 2020 Nov 17. Antimicrob Agents Chemother. 2020. PMID: 32988821 Free PMC article. No abstract available.

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References

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[1] Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, et al. . 2020. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382:1787–1799. doi:10.1056/NEJMoa2001282. - DOI - PMC - PubMed

[2] Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, et al. . 2020. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382:1787–1799. doi:10.1056/NEJMoa2001282. - DOI - PMC - PubMed

[3] Mehra MR, Ruschitzka F, Patel AN. 2020. Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 395:1820. doi:10.1016/S0140-6736(20)31324-6. - DOI - PMC - PubMed

[4] Mehra MR, Ruschitzka F, Patel AN. 2020. Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet 395:1820. doi:10.1016/S0140-6736(20)31324-6. - DOI - PMC - PubMed

[5] Murthy S, Gomersall CD, Fowler RA. 2020. Care for critically ill patients with COVID-19. JAMA 323:1499. doi:10.1001/jama.2020.3633. - DOI - PubMed

[6] Murthy S, Gomersall CD, Fowler RA. 2020. Care for critically ill patients with COVID-19. JAMA 323:1499. doi:10.1001/jama.2020.3633. - DOI - PubMed

[7] Avataneo V, de Nicolò A, Cusato J, Antonucci M, Manca A, Palermiti A, Waitt C, Walimbwa S, Lamorde M, di Perri G, D’Avolio A. 2020. Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease. J Antimicrob Chemother 75:1772–1777. doi:10.1093/jac/dkaa152. - DOI - PMC - PubMed

[8] Avataneo V, de Nicolò A, Cusato J, Antonucci M, Manca A, Palermiti A, Waitt C, Walimbwa S, Lamorde M, di Perri G, D’Avolio A. 2020. Development and validation of a UHPLC-MS/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: a tool for clinical pharmacokinetics of SARS-CoV-2/COVID-19 and Ebola virus disease. J Antimicrob Chemother 75:1772–1777. doi:10.1093/jac/dkaa152. - DOI - PMC - PubMed

[9] Cao Y-C, Deng Q-X, Dai S-X. 2020. Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: an evaluation of the evidence. Travel Med Infect Dis 35:101647. doi:10.1016/j.tmaid.2020.101647. - DOI - PMC - PubMed

[10] Cao Y-C, Deng Q-X, Dai S-X. 2020. Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: an evaluation of the evidence. Travel Med Infect Dis 35:101647. doi:10.1016/j.tmaid.2020.101647. - DOI - PMC - PubMed

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Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19

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Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19

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