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Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis.
Antimicrob Agents Chemother. 2017 03; 61(3)AA

Abstract

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.).

Authors+Show Affiliations

Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands. Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands t.p.c.dorlo@uu.nl saravian@cideim.org.co. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia t.p.c.dorlo@uu.nl saravian@cideim.org.co.

Pub Type(s)

Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27956421

Citation

Castro, María Del Mar, et al. "Pharmacokinetics of Miltefosine in Children and Adults With Cutaneous Leishmaniasis." Antimicrobial Agents and Chemotherapy, vol. 61, no. 3, 2017.
Castro MD, Gomez MA, Kip AE, et al. Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis. Antimicrob Agents Chemother. 2017;61(3).
Castro, M. D., Gomez, M. A., Kip, A. E., Cossio, A., Ortiz, E., Navas, A., Dorlo, T. P., & Saravia, N. G. (2017). Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis. Antimicrobial Agents and Chemotherapy, 61(3). https://doi.org/10.1128/AAC.02198-16
Castro MD, et al. Pharmacokinetics of Miltefosine in Children and Adults With Cutaneous Leishmaniasis. Antimicrob Agents Chemother. 2017;61(3) PubMed PMID: 27956421.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis. AU - Castro,María Del Mar, AU - Gomez,Maria Adelaida, AU - Kip,Anke E, AU - Cossio,Alexandra, AU - Ortiz,Eduardo, AU - Navas,Adriana, AU - Dorlo,Thomas P C, AU - Saravia,Nancy Gore, Y1 - 2017/02/23/ PY - 2016/10/14/received PY - 2016/11/25/accepted PY - 2016/12/14/pubmed PY - 2017/9/13/medline PY - 2016/12/14/entrez KW - children KW - cutaneous leishmaniasis KW - intracellular miltefosine KW - miltefosine KW - pharmacokinetics JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 61 IS - 3 N2 - 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.). SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/27956421/Pharmacokinetics_of_Miltefosine_in_Children_and_Adults_with_Cutaneous_Leishmaniasis_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&amp;pmid=27956421 DB - PRIME DP - Unbound Medicine ER -