Assessing Dose‑Exposure–Response Relationships of Miltefosine in Adults and Children using Physiologically‑Based Pharmacokinetic Modeling Approach

Objectives: Miltefosine is the frst and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with diferences in exposure patterns and cure rates among diferent population groups e.g. ethnicity and age (i.e., children v adults) in clinical trials. In this work, mechanistic population physiologically-based pharmacokinetic (PBPK) models have been developed to study the dose-exposure–response relationship of miltefosine in in silico clinical trials and evaluate the diferences in population groups, particularly children and adults.

Methods: The Simcyp population pharmacokinetics platform was employed to predict miltefosine exposure in plasma and peripheral blood mononuclear cells (PBMCs) in a virtual population under diferent dosing regimens. The cure rate of a simulation was based on the percentage of number of the individual virtual subjects with AUCd0-28>535 µg⋅day/mL in the virtual population.

Results: It is shown that both adult and paediatric PBPK models of miltefosine can be developed to predict the PK data of the clinical trials accurately. There was no signifcant diference in the predicted dose-exposure–response of the miltefosine treatment for diferent simulated ethnicities under the same dose regime and the dose-selection strategies determined the clinical outcome of the miltefosine treatment. A lower cure rate of the miltefosine treatment in paediatrics was predicted because a lower exposure of miltefosine was simulated in virtual paediatric in comparison with adult virtual populations when they received the same dose of the treatment.

Conclusions: The mechanistic PBPK model suggested that the higher fraction of unbound miltefosine in plasma was responsible for a higher probability of failure in paediatrics because of the diference in the distribution of plasma proteins between adults and paediatrics. The developed PBPK models could be used to determine an optimal miltefosine dose regime in future clinical trials.