Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19.
Adenosine Monophosphate
/ analogs & derivatives
Adenosine Triphosphate
/ analogs & derivatives
Aged
Alanine
/ analogs & derivatives
Antiviral Agents
/ pharmacokinetics
Betacoronavirus
COVID-19
Coronavirus Infections
/ diagnosis
Critical Illness
/ therapy
Female
Humans
Male
Pandemics
Pneumonia, Viral
/ diagnosis
Recovery of Function
/ drug effects
SARS-CoV-2
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
26
03
2020
revised:
08
05
2020
accepted:
14
05
2020
pubmed:
2
7
2020
medline:
30
9
2020
entrez:
2
7
2020
Statut:
ppublish
Résumé
Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32607555
pii: 5865507
doi: 10.1093/jac/dkaa239
pmc: PMC7337789
doi:
Substances chimiques
Antiviral Agents
0
remdesivir
3QKI37EEHE
Adenosine Monophosphate
415SHH325A
Adenosine Triphosphate
8L70Q75FXE
GS-441524 triphosphate
AEL0YED4SU
Alanine
OF5P57N2ZX
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2977-2980Investigateurs
Maria Alessandra Abbonizio
(MA)
Chiara Agrati
(C)
Fabrizio Albarello
(F)
Gioia Amadei
(G)
Alessandra Amendola
(A)
Andrea Antinori
(A)
Mario Antonini
(M)
Raffaella Barbaro
(R)
Barbara Bartolini
(B)
Martina Benigni
(M)
Nazario Bevilacqua
(N)
Licia Bordi
(L)
Veronica Bordoni
(V)
Marta Branca
(M)
Paolo Campioni
(P)
Maria Rosaria Capobianchi
(MR)
Cinzia Caporale
(C)
Ilaria Caravella
(I)
Fabrizio Carletti
(F)
Rita Casetti
(R)
Concetta Castilletti
(C)
Roberta Chiappini
(R)
Carmine Ciaralli
(C)
Eleonora Cimini
(E)
Francesca Colavita
(F)
Angela Corpolongo
(A)
Massimo Cristofaro
(M)
Salvatore Curiale
(S)
Alessandra D'Abramo
(A)
Cristina Dantimi
(C)
Alessia De Angelis
(A)
Giada De Angelis
(G)
Rachele Di Lorenzo
(R)
Federica Di Stefano
(F)
Gianpiero D'Offizi
(G)
Federica Ferraro
(F)
Lorena Fiorentini
(L)
Andrea Frustaci
(A)
Paola Gallì
(P)
Gabriele Garotto
(G)
Maria Letizia Giancola
(ML)
Filippo Giansante
(F)
Emanuela Giombini
(E)
Germana Grassi
(G)
Maria Cristina Greci
(MC)
Giuseppe Ippolito
(G)
Eleonora Lalle
(E)
Simone Lanini
(S)
Daniele Lapa
(D)
Luciana Lepore
(L)
Andrea Lucia
(A)
Franco Lufrani
(F)
Manuela Macchione
(M)
Alessandra Marani
(A)
Luisa Marchioni
(L)
Andrea Mariano
(A)
Maria Cristina Marini
(MC)
Micaela Maritti
(M)
Giulia Matusali
(G)
Silvia Meschi
(S)
Francesco Messina
(F)
Chiara Montaldo
(C)
Silvia Murachelli
(S)
Emanuele Nicastri
(E)
Roberto Noto
(R)
Claudia Palazzolo
(C)
Emanuele Pallini
(E)
Fabrizio Palmieri
(F)
Virgilio Passeri
(V)
Federico Pelliccioni
(F)
Antonella Petrecchia
(A)
Ada Petrone
(A)
Nicola Petrosillo
(N)
Elisa Pianura
(E)
Maria Pisciotta
(M)
Silvia Pittalis
(S)
Costanza Proietti
(C)
Vincenzo Puro
(V)
Gabriele Rinonapoli
(G)
Martina Rueca
(M)
Alessandra Sacchi
(A)
Francesco Sanasi
(F)
Carmen Santagata
(C)
Silvana Scarcia
(S)
Vincenzo Schininà
(V)
Paola Scognamiglio
(P)
Laura Scorzolini
(L)
Giulia Stazi
(G)
Francesco Vaia
(F)
Francesco Vairo
(F)
Maria Beatrice Valli
(MB)
Informations de copyright
© 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.
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