Development of a physiologically based pharmacokinetic model for children with severe malnutrition

Severe malnutrition in children remains a global health problem. The pharmacokinetics of drugs are affected by several physiological changes associated with malnutrition. A physiologically based pharmacokinetic (PBPK) models have advantages in relating pharmacokinetic parameters to such physiological changes. The aims of this work were to develop a PBPK model for predicting drug disposition in children with severe malnutrition, using ciprofloxacin as a model drug and (2) to investigate the impact of tissue:plasma partition coefficients (Kp) predicted with different methods on the predictions.
The WBPBPK model was initially developed for healthy adults and then scaled to healthy and malnourished children. The model comprises 13 physiologically realistic compartments namely artery, venous, lungs, liver, kidneys, gut, adipose, skin, muscle, heart, brain, bone, and spleen. A rest compartment was included in the model to compensate for unaccounted mass of drug. The dynamic processes of drug in each organ/tissue were described using linear ordinary differential equations written in the MATLAB program. Physiological parameters for healthy adults and children were compiled from the literature. Kp(s) were calculated using Poulin models [1], Rodgers’ models [2] and the empirical methods [3]. For malnourished children, body weights were predicted using age, height, gender and Z-score taken from the WHO database. Organ/tissue weights were scaled from normal values using scaling factors for each organ. Cardiac output was estimated using body surface area and cardiac index and was subsequently used to calculate organ blood flows. Predictions of pharmacokinetic profiles were compared with observed data taken from the literature.
For healthy adults and children, the predicted versus observed concentration-time profiles were well described with intravenous (IV bolus and short infusion) models. Oral predictions were also in good agreement with literature data but peak concentrations were more rapidly achieved with a higher dose. Unlike the Poulin model, the concentration-time profiles predicted using Kp from the Rodgers models and the empirical methods were similar, and closely resembled the observed data. When models were scaled for malnutrition, inter-individual variability was higher, especially during the absorption phase. However, pharmacokinetic profiles were still adequately described.
A PBPK model was developed successfully for malnourished children. The Rodgers models and the empirical methods are suitable to predict Kp values for ciprofloxacin.