Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19
Authors: Tempestilli Massimo , Caputi Priscilla , Avataneo Valeria , Notari Stefania , Forini Olindo , Scorzolini Laura , Marchioni Luisa , Ascoli Bartoli Tommaso , Castilletti Concetta , Lalle Eleonora , Capobianchi Maria R , Nicastri Emanuele , D’Avolio Antonio , Ippolito Giuseppe , Agrati Chiara ,   the COVID 19 INMI Study Group, Abbonizio Maria Alessandra , Agrati Chiara , Albarello Fabrizio , Amadei Gioia , Amendola Alessandra , Antinori Andrea , Antonini Mario , Barbaro Raffaella , Bartolini Barbara , Benigni Martina , Bevilacqua Nazario , Bordi Licia , Bordoni Veronica , Branca Marta , Campioni Paolo , Capobianchi Maria Rosaria , Caporale Cinzia , Caravella Ilaria , Carletti Fabrizio , Casetti Rita , Castilletti Concetta , Chiappini Roberta , Ciaralli Carmine , Cimini Eleonora , Colavita Francesca , Corpolongo Angela , Cristofaro Massimo , Curiale Salvatore , D’Abramo Alessandra , Dantimi Cristina , De Angelis Alessia , De Angelis Giada , Di Lorenzo Rachele , Di Stefano Federica , D’Offizi Gianpiero , Ferraro Federica , Fiorentini Lorena , Frustaci Andrea , Gallì Paola , Garotto Gabriele , Giancola Maria Letizia , Giansante Filippo , Giombini Emanuela , Grassi Germana , Greci Maria Cristina , Ippolito Giuseppe , Lalle Eleonora , Lanini Simone , Lapa Daniele , Lepore Luciana , Lucia Andrea , Lufrani Franco , Macchione Manuela , Marani Alessandra , Marchioni Luisa , Mariano Andrea , Marini Maria Cristina , Maritti Micaela , Matusali Giulia , Meschi Silvia , Messina Francesco , Montaldo Chiara , Murachelli Silvia , Nicastri Emanuele , Noto Roberto , Palazzolo Claudia , Pallini Emanuele , Palmieri Fabrizio , Passeri Virgilio , Pelliccioni Federico , Petrecchia Antonella , Petrone Ada , Petrosillo Nicola , Pianura Elisa , Pisciotta Maria , Pittalis Silvia , Proietti Costanza , Puro Vincenzo , Rinonapoli Gabriele , Rueca Martina , Sacchi Alessandra , Sanasi Francesco , Santagata Carmen , Scarcia Silvana , Schininà Vincenzo , Scognamiglio Paola , Scorzolini Laura , Stazi Giulia , Vaia Francesco , Vairo Francesco , Valli Maria Beatrice , Abbonizio Maria Alessandra , Agrati Chiara , Albarello Fabrizio , Amadei Gioia , Amendola Alessandra , Antinori Andrea , Antonini Mario , Barbaro Raffaella , Bartolini Barbara , Benigni Martina , Bevilacqua Nazario , Bordi Licia , Bordoni Veronica , Branca Marta , Campioni Paolo , Capobianchi Maria Rosaria , Caporale Cinzia , Caravella Ilaria , Carletti Fabrizio , Casetti Rita , Castilletti Concetta , Chiappini Roberta , Ciaralli Carmine , Cimini Eleonora , Colavita Francesca , Corpolongo Angela , Cristofaro Massimo , Curiale Salvatore , D’Abramo Alessandra , Dantimi Cristina , De Angelis Alessia , De Angelis Giada , Di Lorenzo Rachele , Di Stefano Federica , D’Offizi Gianpiero , Ferraro Federica , Fiorentini Lorena , Frustaci Andrea , Gallì Paola , Garotto Gabriele , Giancola Maria Letizia , Giansante Filippo , Giombini Emanuela , Grassi Germana , Greci Maria Cristina , Ippolito Giuseppe , Lalle Eleonora , Lanini Simone , Lapa Daniele , Lepore Luciana , Lucia Andrea , Lufrani Franco , Macchione Manuela , Marani Alessandra , Marchioni Luisa , Mariano Andrea , Marini Maria Cristina , Maritti Micaela , Matusali Giulia , Meschi Silvia , Messina Francesco , Montaldo Chiara , Murachelli Silvia , Nicastri Emanuele , Noto Roberto , Palazzolo Claudia , Pallini Emanuele , Palmieri Fabrizio , Passeri Virgilio , Pelliccioni Federico , Petrecchia Antonella , Petrone Ada , Petrosillo Nicola , Pianura Elisa , Pisciotta Maria , Pittalis Silvia , Proietti Costanza , Puro Vincenzo , Rinonapoli Gabriele , Rueca Martina , Sacchi Alessandra , Sanasi Francesco , Santagata Carmen , Scarcia Silvana , Schininà Vincenzo , Scognamiglio Paola , Scorzolini Laura , Stazi Giulia , Vaia Francesco , Vairo Francesco , Valli Maria Beatrice 
Published: May 2020

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.