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PBPK modeling of ivermectin—Considerations for the purpose of developing alternative routes to optimize its safety profile
Although single‐dose ivermectin has been widely used in mass‐drug administration programs for onchocerciasis and lymphatic filariasis for many years, ivermectin may have utility as an endectocide with mosquito‐lethal effects at dosages greater and longer than those used to treat helminths. The final...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10196439/ https://www.ncbi.nlm.nih.gov/pubmed/36840414 http://dx.doi.org/10.1002/psp4.12950 |
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author | Rowland Yeo, Karen Wesche, David |
author_facet | Rowland Yeo, Karen Wesche, David |
author_sort | Rowland Yeo, Karen |
collection | PubMed |
description | Although single‐dose ivermectin has been widely used in mass‐drug administration programs for onchocerciasis and lymphatic filariasis for many years, ivermectin may have utility as an endectocide with mosquito‐lethal effects at dosages greater and longer than those used to treat helminths. The final physiologically‐based pharmacokinetic (PBPK) model for ivermectin described here was able to capture, with reasonable accuracy, observed plasma drug concentration‐time profiles and exposures of ivermectin after a single oral dose of the drug in healthy male (dose range 6–30 mg) and female subjects, in both fasted and fed states, in African patients with onchocerciasis (150 μg/kg) and in African children. The PBPK model can be used for further work on lactation, pediatric dosing (considering CYP3A4 and Pg‐p ontogenies), and pregnancy, especially if nonstandard doses will be used. The key findings of our study indicate that absorption of ivermectin may be highly dependent on bile micelle‐mediated solubility. The drug is highly lipophilic and permeable, and its plasma exposure appears to be associated with the body mass index of an individual. These are all factors that need to be considered when extrapolating to more complex oral formulations or alternative routes of administration. Administering lower doses over a longer period may attenuate the dependence on bile micelle‐mediated solubility. With relevant inputs, the verified PBPK model developed here could be used to simulate plasma exposures following administration of ivermectin by complex generics in development. |
format | Online Article Text |
id | pubmed-10196439 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101964392023-05-20 PBPK modeling of ivermectin—Considerations for the purpose of developing alternative routes to optimize its safety profile Rowland Yeo, Karen Wesche, David CPT Pharmacometrics Syst Pharmacol Reviews Although single‐dose ivermectin has been widely used in mass‐drug administration programs for onchocerciasis and lymphatic filariasis for many years, ivermectin may have utility as an endectocide with mosquito‐lethal effects at dosages greater and longer than those used to treat helminths. The final physiologically‐based pharmacokinetic (PBPK) model for ivermectin described here was able to capture, with reasonable accuracy, observed plasma drug concentration‐time profiles and exposures of ivermectin after a single oral dose of the drug in healthy male (dose range 6–30 mg) and female subjects, in both fasted and fed states, in African patients with onchocerciasis (150 μg/kg) and in African children. The PBPK model can be used for further work on lactation, pediatric dosing (considering CYP3A4 and Pg‐p ontogenies), and pregnancy, especially if nonstandard doses will be used. The key findings of our study indicate that absorption of ivermectin may be highly dependent on bile micelle‐mediated solubility. The drug is highly lipophilic and permeable, and its plasma exposure appears to be associated with the body mass index of an individual. These are all factors that need to be considered when extrapolating to more complex oral formulations or alternative routes of administration. Administering lower doses over a longer period may attenuate the dependence on bile micelle‐mediated solubility. With relevant inputs, the verified PBPK model developed here could be used to simulate plasma exposures following administration of ivermectin by complex generics in development. John Wiley and Sons Inc. 2023-03-15 /pmc/articles/PMC10196439/ /pubmed/36840414 http://dx.doi.org/10.1002/psp4.12950 Text en © 2023 Certara UK Limited. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Reviews Rowland Yeo, Karen Wesche, David PBPK modeling of ivermectin—Considerations for the purpose of developing alternative routes to optimize its safety profile |
title | PBPK modeling of ivermectin—Considerations for the purpose of developing alternative routes to optimize its safety profile |
title_full | PBPK modeling of ivermectin—Considerations for the purpose of developing alternative routes to optimize its safety profile |
title_fullStr | PBPK modeling of ivermectin—Considerations for the purpose of developing alternative routes to optimize its safety profile |
title_full_unstemmed | PBPK modeling of ivermectin—Considerations for the purpose of developing alternative routes to optimize its safety profile |
title_short | PBPK modeling of ivermectin—Considerations for the purpose of developing alternative routes to optimize its safety profile |
title_sort | pbpk modeling of ivermectin—considerations for the purpose of developing alternative routes to optimize its safety profile |
topic | Reviews |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10196439/ https://www.ncbi.nlm.nih.gov/pubmed/36840414 http://dx.doi.org/10.1002/psp4.12950 |
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