Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19

Massimo Tempestilli, Priscilla Caputi, Valeria Avataneo, Stefania Notari, Olindo Forini, Laura Scorzolini, Luisa Marchioni, Tommaso Ascoli Bartoli, Concetta Castilletti, Eleonora Lalle, Maria R Capobianchi, Emanuele Nicastri, Antonio D'Avolio, Giuseppe Ippolito, Chiara Agrati, COVID 19 INMI Study Group, Maria Alessandra Abbonizio, Chiara Agrati, Fabrizio Albarello, Gioia Amadei, Alessandra Amendola, Andrea Antinori, Mario Antonini, Raffaella Barbaro, Barbara Bartolini, Martina Benigni, Nazario Bevilacqua, Licia Bordi, Veronica Bordoni, Marta Branca, Paolo Campioni, Maria Rosaria Capobianchi, Cinzia Caporale, Ilaria Caravella, Fabrizio Carletti, Rita Casetti, Concetta Castilletti, Roberta Chiappini, Carmine Ciaralli, Eleonora Cimini, Francesca Colavita, Angela Corpolongo, Massimo Cristofaro, Salvatore Curiale, Alessandra D'Abramo, Cristina Dantimi, Alessia De Angelis, Giada De Angelis, Rachele Di Lorenzo, Federica Di Stefano, Gianpiero D'Offizi, Federica Ferraro, Lorena Fiorentini, Andrea Frustaci, Paola Gallì, Gabriele Garotto, Maria Letizia Giancola, Filippo Giansante, Emanuela Giombini, Germana Grassi, Maria Cristina Greci, Giuseppe Ippolito, Eleonora Lalle, Simone Lanini, Daniele Lapa, Luciana Lepore, Andrea Lucia, Franco Lufrani, Manuela Macchione, Alessandra Marani, Luisa Marchioni, Andrea Mariano, Maria Cristina Marini, Micaela Maritti, Giulia Matusali, Silvia Meschi, Francesco Messina, Chiara Montaldo, Silvia Murachelli, Emanuele Nicastri, Roberto Noto, Claudia Palazzolo, Emanuele Pallini, Fabrizio Palmieri, Virgilio Passeri, Federico Pelliccioni, Antonella Petrecchia, Ada Petrone, Nicola Petrosillo, Elisa Pianura, Maria Pisciotta, Silvia Pittalis, Costanza Proietti, Vincenzo Puro, Gabriele Rinonapoli, Martina Rueca, Alessandra Sacchi, Francesco Sanasi, Carmen Santagata, Silvana Scarcia, Vincenzo Schininà, Paola Scognamiglio, Laura Scorzolini, Giulia Stazi, Francesco Vaia, Francesco Vairo, Maria Beatrice Valli, Massimo Tempestilli, Priscilla Caputi, Valeria Avataneo, Stefania Notari, Olindo Forini, Laura Scorzolini, Luisa Marchioni, Tommaso Ascoli Bartoli, Concetta Castilletti, Eleonora Lalle, Maria R Capobianchi, Emanuele Nicastri, Antonio D'Avolio, Giuseppe Ippolito, Chiara Agrati, COVID 19 INMI Study Group, Maria Alessandra Abbonizio, Chiara Agrati, Fabrizio Albarello, Gioia Amadei, Alessandra Amendola, Andrea Antinori, Mario Antonini, Raffaella Barbaro, Barbara Bartolini, Martina Benigni, Nazario Bevilacqua, Licia Bordi, Veronica Bordoni, Marta Branca, Paolo Campioni, Maria Rosaria Capobianchi, Cinzia Caporale, Ilaria Caravella, Fabrizio Carletti, Rita Casetti, Concetta Castilletti, Roberta Chiappini, Carmine Ciaralli, Eleonora Cimini, Francesca Colavita, Angela Corpolongo, Massimo Cristofaro, Salvatore Curiale, Alessandra D'Abramo, Cristina Dantimi, Alessia De Angelis, Giada De Angelis, Rachele Di Lorenzo, Federica Di Stefano, Gianpiero D'Offizi, Federica Ferraro, Lorena Fiorentini, Andrea Frustaci, Paola Gallì, Gabriele Garotto, Maria Letizia Giancola, Filippo Giansante, Emanuela Giombini, Germana Grassi, Maria Cristina Greci, Giuseppe Ippolito, Eleonora Lalle, Simone Lanini, Daniele Lapa, Luciana Lepore, Andrea Lucia, Franco Lufrani, Manuela Macchione, Alessandra Marani, Luisa Marchioni, Andrea Mariano, Maria Cristina Marini, Micaela Maritti, Giulia Matusali, Silvia Meschi, Francesco Messina, Chiara Montaldo, Silvia Murachelli, Emanuele Nicastri, Roberto Noto, Claudia Palazzolo, Emanuele Pallini, Fabrizio Palmieri, Virgilio Passeri, Federico Pelliccioni, Antonella Petrecchia, Ada Petrone, Nicola Petrosillo, Elisa Pianura, Maria Pisciotta, Silvia Pittalis, Costanza Proietti, Vincenzo Puro, Gabriele Rinonapoli, Martina Rueca, Alessandra Sacchi, Francesco Sanasi, Carmen Santagata, Silvana Scarcia, Vincenzo Schininà, Paola Scognamiglio, Laura Scorzolini, Giulia Stazi, Francesco Vaia, Francesco Vairo, Maria Beatrice Valli

Abstract

Background: Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients.

Objectives: To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients.

Methods: Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method.

Results: We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure.

Conclusions: We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Pharmacokinetics of remdesivir following intravenous administration of multiple doses of remdesivir in critically ill patients (Patient 1 with renal impairment and Patient 2 without renal impairment; mean ± SD measured 3–9 days after remdesivir initiation).
Figure 2.
Figure 2.
Pharmacokinetics of nucleoside analogue GS-441524 following intravenous administration of multiple doses of remdesivir in two critically ill patients (mean ± SD measured 3–9 days after remdesivir initiation). Statistical comparison of GS-441524 plasma concentrations at pharmacokinetic timepoints in Patient 1 (with renal impairment) versus Patient 2 (without renal impairment): *P < 0.05; **P < 0.01; ***P < 0.001 (Mann–Whitney test; P < 0.05 was considered significant).

References

    1. .
    1. .
    1. Li G, De Clercq E.. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov 2020; 19: 149–50.
    1. Siegel D, Hui HC, Doerrfler E. et al. Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J Med Chem 2017; 60: 1648–61.
    1. Wang M, Cao R, Zhang L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30: 269–71.
    1. Sheahan TP, Sims AC, Leist SR. et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020; 11: 222.
    1. Sheahan TP, Sims AC, Graham RL. et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 2017; 9: eaal3653.
    1. Warren TK, Jordan R, Lo MK. et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016; 531: 381–5.
    1. .
    1. Holshue ML, DeBolt C, Lindquist S. et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382: 929–36.
    1. Albarello F, Pianura E, Di Stefano F. et al. 2019-novel coronavirus severe adult respiratory distress syndrome in two cases in Italy: an uncommon radiological presentation. Int J Infect Dis 2020; 93: 192–7.
    1. Mulangu S, Dodd LE, Davey RT Jr. et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 2019; 381: 2293–303.
    1. Avataneo V, de Nicolò A, Cusato J, et al. 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 2020; 10.1093/jac/dkaa152.
    1. Ko WC, Rolain JM, Lee NY. et al. Arguments in favor of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents 2020; 5: 105933.
    1. Grein J, Ohmagari N, Shin D. et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020; 10: doi:10.1056/NEJMoa2007016.
    1. Rizk ML, Zou L, Savic RM. et al. Importance of drug pharmacokinetics at the site of action. Clin Transl Sci 2017; 10: 133–42.
    1. Borst P, Schinkel AH.. P-glycoprotein ABCB1: a major player in drug handling by mammals. J Clin Invest 2013; 123: 4131–3.
    1. Taneva E, Crooker K, Park SH. et al. Differential mechanisms of tenofovir and tenofovir disoproxil fumarate cellular transport and implications for topical preexposure prophylaxis. Antimicrob Agents Chemother 2015; 60: 1667–75.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren