Optimal dosing of miltefosine in children and adults with visceral leishmaniasis

Abstract

Only anecdotal data are available on the pharmacokinetics (PK) of miltefosine in children suffering from visceral leishmaniasis (VL). While failure rates were higher in children with VL, steady-state concentrations appeared lower than those seen with adults. We hypothesized that the current linear dosage (in milligrams per kilogram of body weight) is too low for children and that a new dosing algorithm based on an appropriate body size model would result in an optimal exposure. A population PK analysis was performed on three historic pooled data sets, including Indian children, Indian adults, and European adults. Linear and allometric scaling of PK parameters by either body weight or fat-free mass (FFM) was evaluated for body size models. Based on the developed PK model, a dosing algorithm for miltefosine in children and adults was proposed and evaluated in silico. The population PK model employing allometric scaling fitted best to the pooled miltefosine data. Allometric scaling by FFM reduced between-subject variability, e.g., for drug clearance, from 49.6% to 32.1%. A new allometric miltefosine dosing algorithm was proposed. Exposure to miltefosine was lower in children than adults receiving 2.5 mg/kg/day: a C(max) of 18.8 μg/ml was reached by 90% of adults and 66.7% of children. The allometric daily dose resulted in similar levels of exposure to miltefosine for adults and children. The use of a new allometric dosing algorithm for miltefosine in VL patients results in optimal exposure to miltefosine in both adults and children and might improve clinical outcome in children.

Fig 1

Visual predictive checks for the population pharmacokinetic model employing allometric scaling based on fat-free mass. The dots represent the observed concentrations, the black line indicates the median observed concentration, and the dotted lines show the 5th and 95th percentiles of the observations (indicating the 90% observation interval). The dark gray line indicates the median predicted concentration from 1,000 simulated individuals, and the gray area shows the 90% prediction interval of the model predicted values. The plots are stratified for each different dosing regimen that was used in the respective clinical trials (Adult Indian study, 4 regimens, plots A to D; Pediatric Indian study, 2 regimens, plots E and F; Adult European study, 1 regimen, plot G).

Fig 2

Comparison of miltefosine exposure levels in children and adults: predicted miltefosine concentrations following different dosage regimens. (A) Predicted miltefosine concentration-time curves and intervals for the currently recommended linear 2.5-mg/kg/day miltefosine dose for 28 days. (B) Allometric daily miltefosine dose for 28 days proposed here. The areas of data show the 90% prediction intervals (90% PI; 5th and 95th percentiles) for adults (in gray) and children (between thin black lines); the thicker gray and black lines indicate the median predicted concentrations for adults and children, respectively.

Fig 3

Comparison of miltefosine exposure levels in children and adults: predicted concentration at the end of treatment and the area under the plasma concentration-time curve. These box plots represent distributions of the central miltefosine exposure following from Monte Carlo simulations of 1,000 adults (in gray) and 1,000 children (in white) receiving either the linear miltefosine dose (2.5 mg/kg/day) or the allometric daily miltefosine dose proposed here (Table 4 and equation 6). (A) Concentration at the end of treatment (C_EOT). (B) Area under the concentration-time curve from start to end of treatment (AUC_0-EOT). The pharmacokinetic target to be attained was the minimal adult exposure, set at the value that was attained by 90% of the adults receiving the linear dose (indicated by the dashed line); the percentages above the box plots show the proportions of individuals reaching this target.