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


Background: Convenient, safe, and effective treatments for visceral leishmaniasis in Eastern African children are lacking. Miltefosine, the only oral treatment, failed to achieve adequate cure rates in Eastern Africa, particularly in children, in whom linear dosing (2.5 mg/kg/day for 28 days) resulted in 59% cure rate, with lower systemic miltefosine exposure than in adults. Methods: We conducted a phase-II trial in Kenya and Uganda in 30 children, aged 4-12 years, with visceral leishmaniasis, to test whether 28 days of allometric miltefosine dosing is able to safely achieve a higher and more effective systemic exposure of miltefosine than linear dosing (historical data). Results: Miltefosine accumulated during treatment. Median AUC0-210 and Cmax values were slightly higher than those reported previously for children on linear dosing but not dose-proportionally. Miltefosine exposure at start of treatment was increased, with higher median day-7 plasma concentrations (5.88 vs 2.67 ug/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. Nineteen miltefosine-treatment-related adverse events (AEs) occurred but none caused treatment discontinuation. Two serious AEs occurred, both unrelated to treatment and fully recovering. 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 paediatric patients.

Clinical Infectious Diseases