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Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection

Bamlanivimab and etesevimab are neutralizing antibodies indicated for treatment of coronavirus disease 2019 (COVID‐19) in patients with early mild or moderate disease. We present the use of pharmacokinetic/pharmacodynamic (PK/PD) modeling that characterizes the timecourse of viral load obtained from...

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Autores principales: Chigutsa, Emmanuel, O’Brien, Lisa, Ferguson‐Sells, Lisa, Long, Amanda, Chien, Jenny
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652670/
https://www.ncbi.nlm.nih.gov/pubmed/34514598
http://dx.doi.org/10.1002/cpt.2420
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author Chigutsa, Emmanuel
O’Brien, Lisa
Ferguson‐Sells, Lisa
Long, Amanda
Chien, Jenny
author_facet Chigutsa, Emmanuel
O’Brien, Lisa
Ferguson‐Sells, Lisa
Long, Amanda
Chien, Jenny
author_sort Chigutsa, Emmanuel
collection PubMed
description Bamlanivimab and etesevimab are neutralizing antibodies indicated for treatment of coronavirus disease 2019 (COVID‐19) in patients with early mild or moderate disease. We present the use of pharmacokinetic/pharmacodynamic (PK/PD) modeling that characterizes the timecourse of viral load obtained from 2,970 patients from 2 phase II clinical trials. The model was used for identification of optimal doses that would result in at least 90% of patients achieving serum drug concentrations that result in 90% of maximum drug effect (IC90) for at least 28 days. The serum IC90 (95% confidence interval) was estimated to be 4.2 (3.2–4.3) µg/mL for bamlanivimab and 12.6 (9.7–12.8) µg/mL for etesevimab. Observed clinical trial data confirmed PK and PK/PD model predictions that doses of 700 mg bamlanivimab and 1,400 mg etesevimab would result in maximum reduction in viral load, with no additional effect seen at higher doses. No dose adjustment is recommended as age, sex, race, baseline viral load, and hepatic impairment did not have a significant impact on the PK of the antibodies. Earlier drug administration resulted in greater reductions in viral load, demonstrating the importance of receiving treatment as soon as possible. Relative to placebo, typical reduction in viral load over a 7‐day period was estimated to be 80 or 93% (drug administered 4 days or 1 day after the onset of symptoms, respectively), P < 0.0001. PK/PD modeling and simulation was pivotal throughout the drug development and emergency use authorization process.
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spelling pubmed-86526702021-12-08 Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection Chigutsa, Emmanuel O’Brien, Lisa Ferguson‐Sells, Lisa Long, Amanda Chien, Jenny Clin Pharmacol Ther Research Bamlanivimab and etesevimab are neutralizing antibodies indicated for treatment of coronavirus disease 2019 (COVID‐19) in patients with early mild or moderate disease. We present the use of pharmacokinetic/pharmacodynamic (PK/PD) modeling that characterizes the timecourse of viral load obtained from 2,970 patients from 2 phase II clinical trials. The model was used for identification of optimal doses that would result in at least 90% of patients achieving serum drug concentrations that result in 90% of maximum drug effect (IC90) for at least 28 days. The serum IC90 (95% confidence interval) was estimated to be 4.2 (3.2–4.3) µg/mL for bamlanivimab and 12.6 (9.7–12.8) µg/mL for etesevimab. Observed clinical trial data confirmed PK and PK/PD model predictions that doses of 700 mg bamlanivimab and 1,400 mg etesevimab would result in maximum reduction in viral load, with no additional effect seen at higher doses. No dose adjustment is recommended as age, sex, race, baseline viral load, and hepatic impairment did not have a significant impact on the PK of the antibodies. Earlier drug administration resulted in greater reductions in viral load, demonstrating the importance of receiving treatment as soon as possible. Relative to placebo, typical reduction in viral load over a 7‐day period was estimated to be 80 or 93% (drug administered 4 days or 1 day after the onset of symptoms, respectively), P < 0.0001. PK/PD modeling and simulation was pivotal throughout the drug development and emergency use authorization process. John Wiley and Sons Inc. 2021-09-24 2021-11 /pmc/articles/PMC8652670/ /pubmed/34514598 http://dx.doi.org/10.1002/cpt.2420 Text en © 2021 Eli Lilly and Company. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research
Chigutsa, Emmanuel
O’Brien, Lisa
Ferguson‐Sells, Lisa
Long, Amanda
Chien, Jenny
Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection
title Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection
title_full Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection
title_fullStr Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection
title_full_unstemmed Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection
title_short Population Pharmacokinetics and Pharmacodynamics of the Neutralizing Antibodies Bamlanivimab and Etesevimab in Patients With Mild to Moderate COVID‐19 Infection
title_sort population pharmacokinetics and pharmacodynamics of the neutralizing antibodies bamlanivimab and etesevimab in patients with mild to moderate covid‐19 infection
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652670/
https://www.ncbi.nlm.nih.gov/pubmed/34514598
http://dx.doi.org/10.1002/cpt.2420
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