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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...

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Autores principales: Chotsiri, Palang, Wattanakul, Thanaporn, Hoglund, Richard M., Hanboonkunupakarn, Borimas, Pukrittayakamee, Sasithon, Blessborn, Daniel, Jittamala, Podjanee, White, Nicholas J., Day, Nicholas P.J., Tarning, Joel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
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.
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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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