Cargando…

Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial

Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (M(pro)), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral r...

Descripción completa

Detalles Bibliográficos
Autores principales: Jain, Mamta K., De Lemos, James A., McGuire, Darren K., Ayers, Colby., Eitson, Jennifer L., Sanchez, Claudia L., Kamel, Dena, Meisner, Jessica A., Thomas, Emilia V., Hegde, Anita A., Mocherla, Satish, Strebe, Joslyn K., Li, Xilong, Williams, Noelle S., Xing, Chao, Ahmed, Mahmoud S., Wang, Ping, Sadek, Hesham A., Schoggins, John W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561237/
https://www.ncbi.nlm.nih.gov/pubmed/36249792
http://dx.doi.org/10.3389/fphar.2022.1020123
_version_ 1784807906913288192
author Jain, Mamta K.
De Lemos, James A.
McGuire, Darren K.
Ayers, Colby.
Eitson, Jennifer L.
Sanchez, Claudia L.
Kamel, Dena
Meisner, Jessica A.
Thomas, Emilia V.
Hegde, Anita A.
Mocherla, Satish
Strebe, Joslyn K.
Li, Xilong
Williams, Noelle S.
Xing, Chao
Ahmed, Mahmoud S.
Wang, Ping
Sadek, Hesham A.
Schoggins, John W.
author_facet Jain, Mamta K.
De Lemos, James A.
McGuire, Darren K.
Ayers, Colby.
Eitson, Jennifer L.
Sanchez, Claudia L.
Kamel, Dena
Meisner, Jessica A.
Thomas, Emilia V.
Hegde, Anita A.
Mocherla, Satish
Strebe, Joslyn K.
Li, Xilong
Williams, Noelle S.
Xing, Chao
Ahmed, Mahmoud S.
Wang, Ping
Sadek, Hesham A.
Schoggins, John W.
author_sort Jain, Mamta K.
collection PubMed
description Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (M(pro)), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log(10) viral load was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho −0.45, p = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho −0.54, p = 0.005). Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients.
format Online
Article
Text
id pubmed-9561237
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-95612372022-10-15 Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial Jain, Mamta K. De Lemos, James A. McGuire, Darren K. Ayers, Colby. Eitson, Jennifer L. Sanchez, Claudia L. Kamel, Dena Meisner, Jessica A. Thomas, Emilia V. Hegde, Anita A. Mocherla, Satish Strebe, Joslyn K. Li, Xilong Williams, Noelle S. Xing, Chao Ahmed, Mahmoud S. Wang, Ping Sadek, Hesham A. Schoggins, John W. Front Pharmacol Pharmacology Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (M(pro)), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log(10) viral load was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho −0.45, p = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho −0.54, p = 0.005). Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients. Frontiers Media S.A. 2022-09-30 /pmc/articles/PMC9561237/ /pubmed/36249792 http://dx.doi.org/10.3389/fphar.2022.1020123 Text en Copyright © 2022 Jain, De Lemos, McGuire, Ayers, Eitson, Sanchez, Kamel, Meisner, Thomas, Hegde, Mocherla, Strebe, Li, Williams, Xing, Ahmed, Wang, Sadek and Schoggins. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Jain, Mamta K.
De Lemos, James A.
McGuire, Darren K.
Ayers, Colby.
Eitson, Jennifer L.
Sanchez, Claudia L.
Kamel, Dena
Meisner, Jessica A.
Thomas, Emilia V.
Hegde, Anita A.
Mocherla, Satish
Strebe, Joslyn K.
Li, Xilong
Williams, Noelle S.
Xing, Chao
Ahmed, Mahmoud S.
Wang, Ping
Sadek, Hesham A.
Schoggins, John W.
Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial
title Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial
title_full Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial
title_fullStr Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial
title_full_unstemmed Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial
title_short Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial
title_sort atovaquone for treatment of covid-19: a prospective randomized, double-blind, placebo-controlled clinical trial
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561237/
https://www.ncbi.nlm.nih.gov/pubmed/36249792
http://dx.doi.org/10.3389/fphar.2022.1020123
work_keys_str_mv AT jainmamtak atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT delemosjamesa atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT mcguiredarrenk atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT ayerscolby atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT eitsonjenniferl atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT sanchezclaudial atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT kameldena atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT meisnerjessicaa atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT thomasemiliav atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT hegdeanitaa atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT mocherlasatish atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT strebejoslynk atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT lixilong atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT williamsnoelles atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT xingchao atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT ahmedmahmouds atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT wangping atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT sadekheshama atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial
AT schogginsjohnw atovaquonefortreatmentofcovid19aprospectiverandomizeddoubleblindplacebocontrolledclinicaltrial