Optimal Dosing of Miltefosine in Children and Adults with Leishmaniasis
T.P.C. Dorlo(1,2), P.J. de Vries(1), J.H. Beijnen(2) and A.D.R. Huitema(2)
(1) Division of Infectious Diseases, Tropical Medicine & AIDS, Academic Medical Center, Amsterdam, The Netherlands; (2) Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands
Introduction & Objectives: Pharmacokinetics and –dynamics (PK/PD) of miltefosine in children suffering from visceral leishmaniasis (VL), a fatal neglected parasitic disease, remain ill-characterized. In a large phase 4 trial in India, the number of treatment failures was significantly higher in the pediatric population than in adults (≥12 years) while given a similar dosage of 2.5 mg/kg . Based on this and the previous finding that the mean steady-state concentration in children in the last week of treatment was 24 µg/mL, while in adults 70 µg/mL has been reached , our hypothesis was that the current linear mg/kg dosage is too low for children and that a dose based on allometric scaling might result in a similar exposure to miltefosine between children and adults.
Methods: A population PK analysis was performed, based on pooled PK data from three separate studies, including Indian children (n=39), Indian adults (n=40) and European adults (n=31) with median body weights of 15, 35.5 and 85 kg, respectively. Linear and allometric scaling of CL and V by either total body weight (BW) or fat-free mass (FFM) were evaluated as body size models and compared.
Based on the developed PK model, a dosing-formula for miltefosine in children was proposed. Exposure to miltefosine (time and AUC above various thresholds) and the probability of target attainment (targets were set at exposure values that were achieved by 90% of the adults) after the currently used 2.5 mg/kg dose and the proposed new dosing algorithm were compared between Indian adults and children by Monte Carlo-simulations (n = 1000). All calculations and simulations were performed with software packages NONMEM, R and Pirana.
Results: The population PK model with allometric power scaling fitted best to the pooled miltefosine data. Moreover, allometric scaling by FFM reduced unexplained between-subject variability (BSV): linear scaling by WT or FFM, and allometric scaling by WT or FFM resulted, respectively, in a BSV of 50%, 43%, 35% and 32% for CL, and 43%, 37%, 38% and 34% for V. Based on this allometric model, we proposed a miltefosine dose, scaled with a power 0.75 from a standard adult (60 kg) receiving 150 mg (Dose = 150*(Weight/60)**0.75). Simulated exposure to miltefosine was similar between adults receiving 2.5 mg/kg and children receiving the new allometric dose (e.g. median Time>10 µg/mL was 34.4 and 34.7 days, respectively). More importantly, only 74-78% of the children receiving the currently used linear dose of 2.5 mg/kg achieved a similar minimal systemic exposure as 90% of adults receiving 2.5 mg/kg or children receiving the allometric dose.
Conclusion: The currently applied dose of 2.5 mg/kg results in a significantly lower exposure to miltefosine in children than in adults. We recommend the use of an allometric dose formula for miltefosine in children with leishmaniasis, which results in a similar exposure to miltefosine between adults and children and probably improves clinical outcome in children. An easy-to-use table will be presented for implementation of this dose in the clinic. More data are urgently needed on both PK and PD of miltefosine in VL, certainly in children, to further improve the treatment of this fatal neglected disease.
 J. Infect. Dis. 2007;196:591–8
 Expert Opin. Drug Metab. Toxicol. 2008;4:1209–16