title: Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis.
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)panamensispredominated 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).Leishmaniapersistence 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 vitromiltefosine susceptibility was similar forLeishmaniastrains 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.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: María Del Mar
authors.initials: MD
authors.lastname: Castro
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Maria Adelaida
authors.initials: MA
authors.lastname: Gomez
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.|Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Anke E
authors.initials: AE
authors.lastname: Kip
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cossio
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ortiz
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Adriana
authors.initials: A
authors.lastname: Navas
authors.affiliation: 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.
authors.forename: Thomas P C
authors.initials: TP
authors.lastname: Dorlo
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia t.p.c.dorlo@uu.nl saravian@cideim.org.co.
authors.forename: Nancy Gore
authors.initials: NG
authors.lastname: Saravia
mesh_terms: D000293:Adolescent; D000328:Adult; D000981:Antiprotozoal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007892:Leishmania braziliensis / Q000187:drug effects* / Q000254:growth & development; D018334:Leishmania guyanensis / Q000187:drug effects* / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D021261:Parasitic Sensitivity Tests; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine
keywords: children; cutaneous leishmaniasis; intracellular miltefosine; miltefosine; pharmacokinetics