Pharmacokinetics, Safety, and Efficacy of an Allometric Miltefosine Regimen for the Treatment of Visceral Leishmaniasis in Eastern African Children: An Open-label, Phase II Clinical Trial

Abstract

Background: Convenient, safe, and effective treatments for visceral leishmaniasis in Eastern African children are lacking. Miltefosine, the only oral treatment, failed to achieve adequate efficacy, particularly in children, in whom linear dosing (2.5 mg/kg/day for 28 days) resulted in a 59% cure rate, with lower systemic exposure than in adults.

Methods: We conducted a Phase II trial in 30 children with visceral leishmaniasis, aged 4-12 years, to test whether 28 days of allometric miltefosine dosing safely achieves a higher systemic exposure than linear dosing.

Results: Miltefosine accumulated during treatment. Median areas under the concentration time curve from days 0-210 and plasma maximum concentration values were slightly higher than those reported previously for children on linear dosing, but not dose-proportionally. Miltefosine exposure at the start of treatment was increased, with higher median plasma concentrations on day 7 (5.88 versus 2.67 μg/mL). Concentration-time curves were less variable, avoiding the low levels of exposure observed with linear dosing. The 210-day cure rate was 90% (95% confidence interval, 73-98%), similar to that previously described in adults. There were 19 treatment-related adverse events (AEs), but none caused treatment discontinuation. There were 2 serious AEs: both were unrelated to treatment and both patients were fully recovered.

Conclusions: Allometric miltefosine dosing achieved increased and less-variable exposure than linear dosing, though not reaching the expected exposure levels. The new dosing regimen safely increased the efficacy of miltefosine for Eastern African children with visceral leishmaniasis. Further development of miltefosine should adopt allometric dosing in pediatric patients.

Clinical trials registration: NCT02431143.

Keywords: Eastern African children; allometric regimen; drug pharmacokinetics; miltefosine; visceral leishmaniasis.

Figure 1.

Disposition of patients.

Figure 2.

Individual plasma miltefosine concentration-time profiles: the gray lines indicate the patients who were cured of visceral leishmaniasis, the full black lines indicate the 2 patients who required rescue treatment during follow-up, and the dashed black line indicates the patient who initially failed on treatment. The vertical dotted line shows the end of treatment (day 28).

Figure 3.

Box plots of selected efficacy clinical parameters during treatment (day 0 to day 28) and follow-up. The box plots represent the interquartile ranges, the whiskers represent minimum and maximum values, and the dots outside the whiskers are outlier values. Red lines in the hemoglobin figure represent the lower and upper limits of normal.