Aims and design: An open label, pharmacokinetics clinical trial was conducted to comparatively assess the pharmacokinetics (PK) and explore the pharmacodynamics (PD) of miltefosine in children and adults with cutaneous leishmaniasis in Colombia.
Methods: Sixty patients, 30 children aged 2-12 years and 30 adults aged 18-60 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 six months following completion of treatment, when therapeutic outcome was determined.
Results: Fifty-two patients cured, 5 pediatric patients failed treatment, and 3 participants were lost to follow-up. L.V. panamensis predominated among the strains isolated (42/46, 91%). Non-compartmental analysis demonstrated that plasma and intracellular miltefosine concentrations were overall, lower in children compared to adults. Exposure to miltefosine, estimated by area under the curve and Cmax concentrations, was significantly lower in children both in central and intracellular compartments (p<0.01). Leishmania persistence was detected in 43% of study participants at the end of treatment and 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.
Conclusion: 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 provide bases for optimizing therapeutic regimens for CL in pediatric populations.
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