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Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis

BACKGROUND: Ivermectin (IVM) is a broad–spectrum anthelmintic drug used to treat diseases caused by filarial worms, such as onchocerciasis and lymphatic filariasis (LF). IVM is part of a triple–drug therapy used by the Mass Drug Administration (MDA) as a preventive strategy to eradicate LF in sub–Sa...

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Autores principales: Alshehri, Abdullah, Chhonker, Yashpal S., Bala, Veenu, Edi, Constant, Bjerum, Catherine M., Koudou, Benjamin G., John, Lucy N., Mitjà, Oriol, Marks, Michael, King, Christopher L., Murry, Daryl J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10234547/
https://www.ncbi.nlm.nih.gov/pubmed/37262040
http://dx.doi.org/10.1371/journal.pntd.0011319
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author Alshehri, Abdullah
Chhonker, Yashpal S.
Bala, Veenu
Edi, Constant
Bjerum, Catherine M.
Koudou, Benjamin G.
John, Lucy N.
Mitjà, Oriol
Marks, Michael
King, Christopher L.
Murry, Daryl J.
author_facet Alshehri, Abdullah
Chhonker, Yashpal S.
Bala, Veenu
Edi, Constant
Bjerum, Catherine M.
Koudou, Benjamin G.
John, Lucy N.
Mitjà, Oriol
Marks, Michael
King, Christopher L.
Murry, Daryl J.
author_sort Alshehri, Abdullah
collection PubMed
description BACKGROUND: Ivermectin (IVM) is a broad–spectrum anthelmintic drug used to treat diseases caused by filarial worms, such as onchocerciasis and lymphatic filariasis (LF). IVM is part of a triple–drug therapy used by the Mass Drug Administration (MDA) as a preventive strategy to eradicate LF in sub–Saharan Africa. The drug shows high variability in drug exposure in previous pharmacokinetic studies. This study aims to build a population pharmacokinetic (PopPK) model to identify and quantify the possible sources of the variability of IVM exposure after a single–oral dose in LF–infected subjects and healthy individuals. METHODOLOGY / PRINCIPAL FINDINGS: In this analysis, 724 samples were collected from treatment–naïve Wuchereria bancrofti–infected (n = 32) and uninfected (n = 24) adults living in Côte d’Ivoire who had received one dose of IVM as a part of triple–drug therapy. PopPK analysis was conducted using Phoenix NLME 8.3 software. The Monte Carlo simulation based on the final model was performed to simulate drug exposure among different dosing groups (200 μg/kg, 18 mg, and 36 mg). A two–compartment model with zero–order dose input into the absorption compartment with a lag time function followed by first–order absorption and linear elimination best described the IVM’s pharmacokinetic (PK) parameters. The final model identifies that the PK parameters of IVM are not affected by LF infection. Sex was a significant covariate on the peripheral volume of distribution (Vp/F, 53% lower in men than in women). IVM drug exposure shows linear pharmacokinetic behavior among the simulated dosing groups with similar drug exposure based on sex. CONCLUSION/SIGNIFICANCE: We have developed a PopPk model to describe and identify possible sources of the variability of IVM exposure. To our knowledge, this is the first PopPK study of IVM in patients with LF. TRIAL REGISTRATION: NCT02845713; NCT03664063
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spelling pubmed-102345472023-06-02 Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis Alshehri, Abdullah Chhonker, Yashpal S. Bala, Veenu Edi, Constant Bjerum, Catherine M. Koudou, Benjamin G. John, Lucy N. Mitjà, Oriol Marks, Michael King, Christopher L. Murry, Daryl J. PLoS Negl Trop Dis Research Article BACKGROUND: Ivermectin (IVM) is a broad–spectrum anthelmintic drug used to treat diseases caused by filarial worms, such as onchocerciasis and lymphatic filariasis (LF). IVM is part of a triple–drug therapy used by the Mass Drug Administration (MDA) as a preventive strategy to eradicate LF in sub–Saharan Africa. The drug shows high variability in drug exposure in previous pharmacokinetic studies. This study aims to build a population pharmacokinetic (PopPK) model to identify and quantify the possible sources of the variability of IVM exposure after a single–oral dose in LF–infected subjects and healthy individuals. METHODOLOGY / PRINCIPAL FINDINGS: In this analysis, 724 samples were collected from treatment–naïve Wuchereria bancrofti–infected (n = 32) and uninfected (n = 24) adults living in Côte d’Ivoire who had received one dose of IVM as a part of triple–drug therapy. PopPK analysis was conducted using Phoenix NLME 8.3 software. The Monte Carlo simulation based on the final model was performed to simulate drug exposure among different dosing groups (200 μg/kg, 18 mg, and 36 mg). A two–compartment model with zero–order dose input into the absorption compartment with a lag time function followed by first–order absorption and linear elimination best described the IVM’s pharmacokinetic (PK) parameters. The final model identifies that the PK parameters of IVM are not affected by LF infection. Sex was a significant covariate on the peripheral volume of distribution (Vp/F, 53% lower in men than in women). IVM drug exposure shows linear pharmacokinetic behavior among the simulated dosing groups with similar drug exposure based on sex. CONCLUSION/SIGNIFICANCE: We have developed a PopPk model to describe and identify possible sources of the variability of IVM exposure. To our knowledge, this is the first PopPK study of IVM in patients with LF. TRIAL REGISTRATION: NCT02845713; NCT03664063 Public Library of Science 2023-06-01 /pmc/articles/PMC10234547/ /pubmed/37262040 http://dx.doi.org/10.1371/journal.pntd.0011319 Text en © 2023 Alshehri et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Alshehri, Abdullah
Chhonker, Yashpal S.
Bala, Veenu
Edi, Constant
Bjerum, Catherine M.
Koudou, Benjamin G.
John, Lucy N.
Mitjà, Oriol
Marks, Michael
King, Christopher L.
Murry, Daryl J.
Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis
title Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis
title_full Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis
title_fullStr Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis
title_full_unstemmed Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis
title_short Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis
title_sort population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10234547/
https://www.ncbi.nlm.nih.gov/pubmed/37262040
http://dx.doi.org/10.1371/journal.pntd.0011319
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