Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside
Background To accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. Emodepside has shown macrofilaricidal activity against a variety of nematodes and is currently under clinical development for the treatment of onchocerc...
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ftdoajarticles:oai:doaj.org/article:c7a5f129570342808d05e3631babd9f3 2023-05-15T15:15:36+02:00 Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside Frauke Assmus Richard M. Hoglund Frédéric Monnot Sabine Specht Ivan Scandale Joel Tarning 2022-03-01T00:00:00Z https://doaj.org/article/c7a5f129570342808d05e3631babd9f3 EN eng Public Library of Science (PLoS) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912909/?tool=EBI https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 https://doaj.org/article/c7a5f129570342808d05e3631babd9f3 PLoS Neglected Tropical Diseases, Vol 16, Iss 3 (2022) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2022 ftdoajarticles 2022-12-31T01:39:22Z Background To accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. Emodepside has shown macrofilaricidal activity against a variety of nematodes and is currently under clinical development for the treatment of onchocerciasis. The aims of this study were i) to characterize the population pharmacokinetic properties of emodepside, ii) to link its exposure to adverse events in healthy volunteers, and iii) to propose an optimized dosing regimen for a planned phase II study in onchocerciasis patients. Methodology / Principal findings Plasma concentration-time profiles and adverse event data were obtained from 142 subjects enrolled in three phase I studies, including a single-dose, and a multiple-dose, dose-escalation study as well as a relative bioavailability study. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic properties of emodepside. Logistic regression modeling was used to link exposure to drug-related treatment-emergent adverse events (TEAEs). Emodepside pharmacokinetics were well described by a transit-absorption model, followed by a 3-compartment disposition model. Body weight was included as an allometric function and both food and formulation had a significant impact on absorption rate and relative bioavailability. All drug-related TEAEs were transient, and mild or moderate in severity. An increase in peak plasma concentration was associated with an increase in the odds of experiencing a drug-related TEAE of interest. Conclusions/Significance Pharmacokinetic modeling and simulation was used to derive an optimized, body weight-based dosing regimen, which allows for achievement of extended emodepside exposures above target concentrations while maintaining acceptable tolerability margins. Author summary Onchocerciasis (‘River Blindness’), is a worm infection common in sub-Saharan Africa. More than 20 million people are suffering from the disease which can lead to disfiguring skin disease, ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
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English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Frauke Assmus Richard M. Hoglund Frédéric Monnot Sabine Specht Ivan Scandale Joel Tarning Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Background To accelerate the progress towards onchocerciasis elimination, a macrofilaricidal drug that kills the adult parasite is urgently needed. Emodepside has shown macrofilaricidal activity against a variety of nematodes and is currently under clinical development for the treatment of onchocerciasis. The aims of this study were i) to characterize the population pharmacokinetic properties of emodepside, ii) to link its exposure to adverse events in healthy volunteers, and iii) to propose an optimized dosing regimen for a planned phase II study in onchocerciasis patients. Methodology / Principal findings Plasma concentration-time profiles and adverse event data were obtained from 142 subjects enrolled in three phase I studies, including a single-dose, and a multiple-dose, dose-escalation study as well as a relative bioavailability study. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic properties of emodepside. Logistic regression modeling was used to link exposure to drug-related treatment-emergent adverse events (TEAEs). Emodepside pharmacokinetics were well described by a transit-absorption model, followed by a 3-compartment disposition model. Body weight was included as an allometric function and both food and formulation had a significant impact on absorption rate and relative bioavailability. All drug-related TEAEs were transient, and mild or moderate in severity. An increase in peak plasma concentration was associated with an increase in the odds of experiencing a drug-related TEAE of interest. Conclusions/Significance Pharmacokinetic modeling and simulation was used to derive an optimized, body weight-based dosing regimen, which allows for achievement of extended emodepside exposures above target concentrations while maintaining acceptable tolerability margins. Author summary Onchocerciasis (‘River Blindness’), is a worm infection common in sub-Saharan Africa. More than 20 million people are suffering from the disease which can lead to disfiguring skin disease, ... |
format |
Article in Journal/Newspaper |
author |
Frauke Assmus Richard M. Hoglund Frédéric Monnot Sabine Specht Ivan Scandale Joel Tarning |
author_facet |
Frauke Assmus Richard M. Hoglund Frédéric Monnot Sabine Specht Ivan Scandale Joel Tarning |
author_sort |
Frauke Assmus |
title |
Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside |
title_short |
Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside |
title_full |
Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside |
title_fullStr |
Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside |
title_full_unstemmed |
Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside |
title_sort |
drug development for the treatment of onchocerciasis: population pharmacokinetic and adverse events modeling of emodepside |
publisher |
Public Library of Science (PLoS) |
publishDate |
2022 |
url |
https://doaj.org/article/c7a5f129570342808d05e3631babd9f3 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 16, Iss 3 (2022) |
op_relation |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912909/?tool=EBI https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 https://doaj.org/article/c7a5f129570342808d05e3631babd9f3 |
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1766345958974554112 |