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Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing
Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimiz...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153844/ https://www.ncbi.nlm.nih.gov/pubmed/30038039 http://dx.doi.org/10.1128/AAC.02193-17 |
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author | Ali, Ali Mohamed Penny, Melissa A. Smith, Thomas A. Workman, Lesley Sasi, Philip Adjei, George O. Aweeka, Francesca Kiechel, Jean-René Jullien, Vincent Rijken, Marcus J. McGready, Rose Mwesigwa, Julia Kristensen, Kim Stepniewska, Kasia Tarning, Joel Barnes, Karen I. Denti, Paolo |
author_facet | Ali, Ali Mohamed Penny, Melissa A. Smith, Thomas A. Workman, Lesley Sasi, Philip Adjei, George O. Aweeka, Francesca Kiechel, Jean-René Jullien, Vincent Rijken, Marcus J. McGready, Rose Mwesigwa, Julia Kristensen, Kim Stepniewska, Kasia Tarning, Joel Barnes, Karen I. Denti, Paolo |
author_sort | Ali, Ali Mohamed |
collection | PubMed |
description | Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation. |
format | Online Article Text |
id | pubmed-6153844 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-61538442018-09-28 Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing Ali, Ali Mohamed Penny, Melissa A. Smith, Thomas A. Workman, Lesley Sasi, Philip Adjei, George O. Aweeka, Francesca Kiechel, Jean-René Jullien, Vincent Rijken, Marcus J. McGready, Rose Mwesigwa, Julia Kristensen, Kim Stepniewska, Kasia Tarning, Joel Barnes, Karen I. Denti, Paolo Antimicrob Agents Chemother Pharmacology Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation. American Society for Microbiology 2018-09-24 /pmc/articles/PMC6153844/ /pubmed/30038039 http://dx.doi.org/10.1128/AAC.02193-17 Text en Copyright © 2018 Ali et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Pharmacology Ali, Ali Mohamed Penny, Melissa A. Smith, Thomas A. Workman, Lesley Sasi, Philip Adjei, George O. Aweeka, Francesca Kiechel, Jean-René Jullien, Vincent Rijken, Marcus J. McGready, Rose Mwesigwa, Julia Kristensen, Kim Stepniewska, Kasia Tarning, Joel Barnes, Karen I. Denti, Paolo Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing |
title | Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing |
title_full | Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing |
title_fullStr | Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing |
title_full_unstemmed | Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing |
title_short | Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing |
title_sort | population pharmacokinetics of the antimalarial amodiaquine: a pooled analysis to optimize dosing |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153844/ https://www.ncbi.nlm.nih.gov/pubmed/30038039 http://dx.doi.org/10.1128/AAC.02193-17 |
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