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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2018
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.
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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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