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Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria

BACKGROUND: Fever is an inherent symptom of malaria in both adults and children. Paracetamol (acetaminophen) is the recommended antipyretic as it is inexpensive, widely available and has a good safety profile, but patients may not be able to take the oral drug reliably. A comparison between the phar...

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Autores principales: Wattanakul, Thanaporn, Teerapong, Pramote, Plewes, Katherine, Newton, Paul N., Chierakul, Wirongrong, Silamut, Kamolrat, Chotivanich, Kesinee, Ruengweerayut, Ronnatrai, White, Nicholas J., Dondorp, Arjen M., Tarning, Joel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847232/
https://www.ncbi.nlm.nih.gov/pubmed/27118212
http://dx.doi.org/10.1186/s12936-016-1283-9
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author Wattanakul, Thanaporn
Teerapong, Pramote
Plewes, Katherine
Newton, Paul N.
Chierakul, Wirongrong
Silamut, Kamolrat
Chotivanich, Kesinee
Ruengweerayut, Ronnatrai
White, Nicholas J.
Dondorp, Arjen M.
Tarning, Joel
author_facet Wattanakul, Thanaporn
Teerapong, Pramote
Plewes, Katherine
Newton, Paul N.
Chierakul, Wirongrong
Silamut, Kamolrat
Chotivanich, Kesinee
Ruengweerayut, Ronnatrai
White, Nicholas J.
Dondorp, Arjen M.
Tarning, Joel
author_sort Wattanakul, Thanaporn
collection PubMed
description BACKGROUND: Fever is an inherent symptom of malaria in both adults and children. Paracetamol (acetaminophen) is the recommended antipyretic as it is inexpensive, widely available and has a good safety profile, but patients may not be able to take the oral drug reliably. A comparison between the pharmacokinetics of oral syrup and intramuscular paracetamol given to patients with acute falciparum malaria and high body temperature was performed. METHODS: A randomized, open-label, two-treatment, crossover, pharmacokinetic study of paracetamol dosed orally and intramuscularly was conducted. Twenty-one adult patients with uncomplicated falciparum malaria were randomized to receive a single 600 mg dose of paracetamol either as syrup or intramuscular injection on day 0 followed by a single dose administered by the alternative route on day 1. Paracetamol plasma concentrations were quantified frequently and modelled simultaneously using nonlinear mixed-effects modelling. The final population pharmacokinetic model was used for dose optimization simulations. Relationships between paracetamol concentrations with temperature and parasite half-life were investigated using linear and non-linear regression analyses. RESULTS: The population pharmacokinetic properties of paracetamol were best described by a two-compartment disposition model, with zero-order and first-order absorption for intramuscular and oral syrup administration, respectively. The relative bioavailability of oral syrup was 84.4 % (95 % CI 68.2–95.1 %) compared to intramuscular administration. Dosing simulations showed that 1000 mg of intramuscular or oral syrup administered six-hourly reached therapeutic steady state concentrations for antipyresis, but more favourable concentration–time profiles were achieved with a loading dose of 1500 mg, followed by a 1000 mg maintenance dose. This ensured that maximum therapeutic concentrations were reached rapidly during the first 6 h. No significant relationships between paracetamol concentrations and temperature or parasite half-life were found. CONCLUSIONS: Paracetamol plasma concentrations after oral syrup and intramuscular administration in patients with acute falciparum malaria were described successfully by a two-compartment disposition model. Relative oral bioavailability compared to intramuscular dosing was estimated as 84.4 % (95 % CI 68.2–95.1 %). Dosing simulations showed that a loading dose followed by six-hourly dosing intervals reduced the time delay to reach therapeutic drug levels after both routes of administration. The safety and efficacy of loading dose paracetamol antipyretic regimens now needs to be established in larger studies.
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spelling pubmed-48472322016-04-28 Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria Wattanakul, Thanaporn Teerapong, Pramote Plewes, Katherine Newton, Paul N. Chierakul, Wirongrong Silamut, Kamolrat Chotivanich, Kesinee Ruengweerayut, Ronnatrai White, Nicholas J. Dondorp, Arjen M. Tarning, Joel Malar J Research BACKGROUND: Fever is an inherent symptom of malaria in both adults and children. Paracetamol (acetaminophen) is the recommended antipyretic as it is inexpensive, widely available and has a good safety profile, but patients may not be able to take the oral drug reliably. A comparison between the pharmacokinetics of oral syrup and intramuscular paracetamol given to patients with acute falciparum malaria and high body temperature was performed. METHODS: A randomized, open-label, two-treatment, crossover, pharmacokinetic study of paracetamol dosed orally and intramuscularly was conducted. Twenty-one adult patients with uncomplicated falciparum malaria were randomized to receive a single 600 mg dose of paracetamol either as syrup or intramuscular injection on day 0 followed by a single dose administered by the alternative route on day 1. Paracetamol plasma concentrations were quantified frequently and modelled simultaneously using nonlinear mixed-effects modelling. The final population pharmacokinetic model was used for dose optimization simulations. Relationships between paracetamol concentrations with temperature and parasite half-life were investigated using linear and non-linear regression analyses. RESULTS: The population pharmacokinetic properties of paracetamol were best described by a two-compartment disposition model, with zero-order and first-order absorption for intramuscular and oral syrup administration, respectively. The relative bioavailability of oral syrup was 84.4 % (95 % CI 68.2–95.1 %) compared to intramuscular administration. Dosing simulations showed that 1000 mg of intramuscular or oral syrup administered six-hourly reached therapeutic steady state concentrations for antipyresis, but more favourable concentration–time profiles were achieved with a loading dose of 1500 mg, followed by a 1000 mg maintenance dose. This ensured that maximum therapeutic concentrations were reached rapidly during the first 6 h. No significant relationships between paracetamol concentrations and temperature or parasite half-life were found. CONCLUSIONS: Paracetamol plasma concentrations after oral syrup and intramuscular administration in patients with acute falciparum malaria were described successfully by a two-compartment disposition model. Relative oral bioavailability compared to intramuscular dosing was estimated as 84.4 % (95 % CI 68.2–95.1 %). Dosing simulations showed that a loading dose followed by six-hourly dosing intervals reduced the time delay to reach therapeutic drug levels after both routes of administration. The safety and efficacy of loading dose paracetamol antipyretic regimens now needs to be established in larger studies. BioMed Central 2016-04-27 /pmc/articles/PMC4847232/ /pubmed/27118212 http://dx.doi.org/10.1186/s12936-016-1283-9 Text en © Wattanakul et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Wattanakul, Thanaporn
Teerapong, Pramote
Plewes, Katherine
Newton, Paul N.
Chierakul, Wirongrong
Silamut, Kamolrat
Chotivanich, Kesinee
Ruengweerayut, Ronnatrai
White, Nicholas J.
Dondorp, Arjen M.
Tarning, Joel
Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria
title Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria
title_full Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria
title_fullStr Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria
title_full_unstemmed Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria
title_short Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria
title_sort pharmacokinetic properties of intramuscular versus oral syrup paracetamol in plasmodium falciparum malaria
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847232/
https://www.ncbi.nlm.nih.gov/pubmed/27118212
http://dx.doi.org/10.1186/s12936-016-1283-9
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