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Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers
AIMS: The aims of the present study were to evaluate the pharmacokinetic properties of dihydroartemisinin (DHA) and piperaquine, potential drug–drug interactions with concomitant primaquine treatment, and piperaquine effects on the electrocardiogram in healthy volunteers. METHODS: The population pha...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698590/ https://www.ncbi.nlm.nih.gov/pubmed/28695570 http://dx.doi.org/10.1111/bcp.13372 |
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author | Chotsiri, Palang Wattanakul, Thanaporn Hoglund, Richard M. Hanboonkunupakarn, Borimas Pukrittayakamee, Sasithon Blessborn, Daniel Jittamala, Podjanee White, Nicholas J. Day, Nicholas P.J. Tarning, Joel |
author_facet | Chotsiri, Palang Wattanakul, Thanaporn Hoglund, Richard M. Hanboonkunupakarn, Borimas Pukrittayakamee, Sasithon Blessborn, Daniel Jittamala, Podjanee White, Nicholas J. Day, Nicholas P.J. Tarning, Joel |
author_sort | Chotsiri, Palang |
collection | PubMed |
description | AIMS: The aims of the present study were to evaluate the pharmacokinetic properties of dihydroartemisinin (DHA) and piperaquine, potential drug–drug interactions with concomitant primaquine treatment, and piperaquine effects on the electrocardiogram in healthy volunteers. METHODS: The population pharmacokinetic properties of DHA and piperaquine were assessed in 16 healthy Thai adults using an open‐label, randomized, crossover study. Drug concentration–time data and electrocardiographic measurements were evaluated with nonlinear mixed‐effects modelling. RESULTS: The developed models described DHA and piperaquine population pharmacokinetics accurately. Concomitant treatment with primaquine did not affect the pharmacokinetic properties of DHA or piperaquine. A linear pharmacokinetic–pharmacodynamic model described satisfactorily the relationship between the individually corrected QT intervals and piperaquine concentrations; the population mean QT interval increased by 4.17 ms per 100 ng ml(–1) increase in piperaquine plasma concentration. Simulations from the final model showed that monthly and bimonthly mass drug administration in healthy subjects would result in median maximum QT interval prolongations of 18.9 ms and 16.8 ms, respectively, and would be very unlikely to result in prolongation of more than 50 ms. A single low dose of primaquine can be added safely to the existing DHA–piperaquine treatment in areas of multiresistant Plasmodium falciparum malaria. CONCLUSIONS: Pharmacokinetic–pharmacodynamic modelling and simulation in healthy adult volunteers suggested that therapeutic doses of DHA–piperaquine in the prevention or treatment of P. falciparum malaria are unlikely to be associated with dangerous QT prolongation. |
format | Online Article Text |
id | pubmed-5698590 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-56985902017-11-29 Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers Chotsiri, Palang Wattanakul, Thanaporn Hoglund, Richard M. Hanboonkunupakarn, Borimas Pukrittayakamee, Sasithon Blessborn, Daniel Jittamala, Podjanee White, Nicholas J. Day, Nicholas P.J. Tarning, Joel Br J Clin Pharmacol Pharmacokinetic Dynamic Relationships AIMS: The aims of the present study were to evaluate the pharmacokinetic properties of dihydroartemisinin (DHA) and piperaquine, potential drug–drug interactions with concomitant primaquine treatment, and piperaquine effects on the electrocardiogram in healthy volunteers. METHODS: The population pharmacokinetic properties of DHA and piperaquine were assessed in 16 healthy Thai adults using an open‐label, randomized, crossover study. Drug concentration–time data and electrocardiographic measurements were evaluated with nonlinear mixed‐effects modelling. RESULTS: The developed models described DHA and piperaquine population pharmacokinetics accurately. Concomitant treatment with primaquine did not affect the pharmacokinetic properties of DHA or piperaquine. A linear pharmacokinetic–pharmacodynamic model described satisfactorily the relationship between the individually corrected QT intervals and piperaquine concentrations; the population mean QT interval increased by 4.17 ms per 100 ng ml(–1) increase in piperaquine plasma concentration. Simulations from the final model showed that monthly and bimonthly mass drug administration in healthy subjects would result in median maximum QT interval prolongations of 18.9 ms and 16.8 ms, respectively, and would be very unlikely to result in prolongation of more than 50 ms. A single low dose of primaquine can be added safely to the existing DHA–piperaquine treatment in areas of multiresistant Plasmodium falciparum malaria. CONCLUSIONS: Pharmacokinetic–pharmacodynamic modelling and simulation in healthy adult volunteers suggested that therapeutic doses of DHA–piperaquine in the prevention or treatment of P. falciparum malaria are unlikely to be associated with dangerous QT prolongation. John Wiley and Sons Inc. 2017-08-16 2017-12 /pmc/articles/PMC5698590/ /pubmed/28695570 http://dx.doi.org/10.1111/bcp.13372 Text en © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Pharmacokinetic Dynamic Relationships Chotsiri, Palang Wattanakul, Thanaporn Hoglund, Richard M. Hanboonkunupakarn, Borimas Pukrittayakamee, Sasithon Blessborn, Daniel Jittamala, Podjanee White, Nicholas J. Day, Nicholas P.J. Tarning, Joel Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers |
title | Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers |
title_full | Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers |
title_fullStr | Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers |
title_full_unstemmed | Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers |
title_short | Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers |
title_sort | population pharmacokinetics and electrocardiographic effects of dihydroartemisinin–piperaquine in healthy volunteers |
topic | Pharmacokinetic Dynamic Relationships |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698590/ https://www.ncbi.nlm.nih.gov/pubmed/28695570 http://dx.doi.org/10.1111/bcp.13372 |
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