Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development
Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmac...
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ftdoajarticles:oai:doaj.org/article:5789aec589df4b05b5d078352eb6216d 2023-05-15T15:16:38+02:00 Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development Zaloumis Sophie Humberstone Andrew Charman Susan A Price Ric N Moehrle Joerg Gamo-Benito Javier McCaw James Jamsen Kris M Smith Katherine Simpson Julie A 2012-08-01T00:00:00Z https://doi.org/10.1186/1475-2875-11-303 https://doaj.org/article/5789aec589df4b05b5d078352eb6216d EN eng BMC http://www.malariajournal.com/content/11/1/303 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-11-303 1475-2875 https://doaj.org/article/5789aec589df4b05b5d078352eb6216d Malaria Journal, Vol 11, Iss 1, p 303 (2012) Plasmodium falciparum Pharmacokinetic-pharmacodynamic model Anti-malarial combination therapy Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2012 ftdoajarticles https://doi.org/10.1186/1475-2875-11-303 2022-12-31T02:01:45Z Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect ( in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous). Conclusions This ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 11 1 |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
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English |
topic |
Plasmodium falciparum Pharmacokinetic-pharmacodynamic model Anti-malarial combination therapy Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
spellingShingle |
Plasmodium falciparum Pharmacokinetic-pharmacodynamic model Anti-malarial combination therapy Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Zaloumis Sophie Humberstone Andrew Charman Susan A Price Ric N Moehrle Joerg Gamo-Benito Javier McCaw James Jamsen Kris M Smith Katherine Simpson Julie A Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development |
topic_facet |
Plasmodium falciparum Pharmacokinetic-pharmacodynamic model Anti-malarial combination therapy Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect ( in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous). Conclusions This ... |
format |
Article in Journal/Newspaper |
author |
Zaloumis Sophie Humberstone Andrew Charman Susan A Price Ric N Moehrle Joerg Gamo-Benito Javier McCaw James Jamsen Kris M Smith Katherine Simpson Julie A |
author_facet |
Zaloumis Sophie Humberstone Andrew Charman Susan A Price Ric N Moehrle Joerg Gamo-Benito Javier McCaw James Jamsen Kris M Smith Katherine Simpson Julie A |
author_sort |
Zaloumis Sophie |
title |
Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development |
title_short |
Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development |
title_full |
Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development |
title_fullStr |
Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development |
title_full_unstemmed |
Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development |
title_sort |
assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development |
publisher |
BMC |
publishDate |
2012 |
url |
https://doi.org/10.1186/1475-2875-11-303 https://doaj.org/article/5789aec589df4b05b5d078352eb6216d |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 11, Iss 1, p 303 (2012) |
op_relation |
http://www.malariajournal.com/content/11/1/303 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-11-303 1475-2875 https://doaj.org/article/5789aec589df4b05b5d078352eb6216d |
op_doi |
https://doi.org/10.1186/1475-2875-11-303 |
container_title |
Malaria Journal |
container_volume |
11 |
container_issue |
1 |
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1766346940673425408 |