Dual Physiologically Based Pharmacokinetic Model of Liposomal and Nonliposomal Amphotericin B Disposition

Purpose To investigate the biodistribution of amphotericin B (AmB) in mice and rats following administration of liposomal AmB (AmBisomeA (R)) using a physiologically-based pharmacokinetic (PBPK) modeling framework and to utilize this approach for predicting AmBisomeA (R) pharmacokinetics in human tissues. Methods AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of nonliposomal and liposomal AmB to mice and rats, were extracted from literature. The whole-body PBPK model was constructed and incorporated nonliposomal and liposomal subcompartments. Various structural models for individual organs were evaluated. Allometric relationships were incorporated into the model to scale parameters based on species body weight. Results A non-Michaelis-Menten mechanism was included into the structure of the liver and spleen liposomal compartments to describe saturable uptake of particles by the reticuloendothelial system. The model successfully described plasma and tissue pharmacokinetics of AmB after administration of AmBisomeA (R) to rats and mice. Conclusions The dual PBPK model demonstrated good predictive performance by reasonably simulating AmB exposure in human tissues. This modeling framework can be potentially utilized for optimizing AmBisomeA (R) therapy in humans and for investigating pathophysiological factors controlling AmB pharmacokinetics and pharmacodynamics.