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Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis

An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis (CL) in Colombia. Sixty patients, 30 children aged 2 to 12 years and 30 adults aged 18 to 60 years,...

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Autores principales: Castro, María del Mar, Gomez, Maria Adelaida, Kip, Anke E., Cossio, Alexandra, Ortiz, Eduardo, Navas, Adriana, Dorlo, Thomas P. C., Saravia, Nancy Gore
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328512/
https://www.ncbi.nlm.nih.gov/pubmed/27956421
http://dx.doi.org/10.1128/AAC.02198-16
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author Castro, María del Mar
Gomez, Maria Adelaida
Kip, Anke E.
Cossio, Alexandra
Ortiz, Eduardo
Navas, Adriana
Dorlo, Thomas P. C.
Saravia, Nancy Gore
author_facet Castro, María del Mar
Gomez, Maria Adelaida
Kip, Anke E.
Cossio, Alexandra
Ortiz, Eduardo
Navas, Adriana
Dorlo, Thomas P. C.
Saravia, Nancy Gore
author_sort Castro, María del Mar
collection PubMed
description An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis (CL) in Colombia. Sixty patients, 30 children aged 2 to 12 years and 30 adults aged 18 to 60 years, were enrolled. Participants received miltefosine (Impavido) at a nominal dose of 2.5 mg/kg/day for 28 days. Miltefosine concentrations were measured in plasma and peripheral blood mononuclear cells by liquid chromatography-tandem mass spectrometry of samples obtained during treatment and up to 6 months following completion of treatment, when therapeutic outcome was determined. Fifty-two patients were cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up. Leishmania (Viannia) panamensis predominated among the strains isolated (42/46; 91%). Noncompartmental analysis demonstrated that plasma and intracellular miltefosine concentrations were, overall, lower in children than in adults. Exposure to miltefosine, estimated by area under the concentration-time curve and maximum concentration, was significantly lower in children in both the central and intracellular compartments (P < 0.01). Leishmania persistence was detected in 43% of study participants at the end of treatment and in 27% at 90 days after initiation of treatment. Clinical response was not dependent on parasite elimination. In vitro miltefosine susceptibility was similar for Leishmania strains from adults and children. Our results document PK differences for miltefosine in children and adults with cutaneous leishmaniasis that affect drug exposure and could influence the outcome of treatment, and they provide bases for optimizing therapeutic regimens for CL in pediatric populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01462500.)
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spelling pubmed-53285122017-03-09 Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis Castro, María del Mar Gomez, Maria Adelaida Kip, Anke E. Cossio, Alexandra Ortiz, Eduardo Navas, Adriana Dorlo, Thomas P. C. Saravia, Nancy Gore Antimicrob Agents Chemother Pharmacology An open-label pharmacokinetics (PK) clinical trial was conducted to comparatively assess the PK and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis (CL) in Colombia. Sixty patients, 30 children aged 2 to 12 years and 30 adults aged 18 to 60 years, were enrolled. Participants received miltefosine (Impavido) at a nominal dose of 2.5 mg/kg/day for 28 days. Miltefosine concentrations were measured in plasma and peripheral blood mononuclear cells by liquid chromatography-tandem mass spectrometry of samples obtained during treatment and up to 6 months following completion of treatment, when therapeutic outcome was determined. Fifty-two patients were cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up. Leishmania (Viannia) panamensis predominated among the strains isolated (42/46; 91%). Noncompartmental analysis demonstrated that plasma and intracellular miltefosine concentrations were, overall, lower in children than in adults. Exposure to miltefosine, estimated by area under the concentration-time curve and maximum concentration, was significantly lower in children in both the central and intracellular compartments (P < 0.01). Leishmania persistence was detected in 43% of study participants at the end of treatment and in 27% at 90 days after initiation of treatment. Clinical response was not dependent on parasite elimination. In vitro miltefosine susceptibility was similar for Leishmania strains from adults and children. Our results document PK differences for miltefosine in children and adults with cutaneous leishmaniasis that affect drug exposure and could influence the outcome of treatment, and they provide bases for optimizing therapeutic regimens for CL in pediatric populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01462500.) American Society for Microbiology 2017-02-23 /pmc/articles/PMC5328512/ /pubmed/27956421 http://dx.doi.org/10.1128/AAC.02198-16 Text en Copyright © 2017 Castro et al. http://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 (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Pharmacology
Castro, María del Mar
Gomez, Maria Adelaida
Kip, Anke E.
Cossio, Alexandra
Ortiz, Eduardo
Navas, Adriana
Dorlo, Thomas P. C.
Saravia, Nancy Gore
Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
title Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
title_full Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
title_fullStr Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
title_full_unstemmed Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
title_short Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis
title_sort pharmacokinetics of miltefosine in children and adults with cutaneous leishmaniasis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328512/
https://www.ncbi.nlm.nih.gov/pubmed/27956421
http://dx.doi.org/10.1128/AAC.02198-16
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