title: Dual physiologically based pharmacokinetic model of liposomal and nonliposomal amphotericin B disposition.
abstract: OBJECTIVE
  To investigate the biodistribution of amphotericin B (AmB) in mice and rats following administration of liposomal AmB (AmBisome®) using a physiologically-based pharmacokinetic (PBPK) modeling framework and to utilize this approach for predicting AmBisome® 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 AmBisome® 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 AmBisome® therapy in humans and for investigating pathophysiological factors controlling AmB pharmacokinetics and pharmacodynamics.
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey,, 160 Frelinghuysen Rd., Piscataway, New Jersey, 08854, USA, lkagan@pharmacy.rutgers.edu.
authors.forename: Leonid
authors.initials: L
authors.lastname: Kagan
authors.forename: Pavel
authors.initials: P
authors.lastname: Gershkovich
authors.forename: Kishor M
authors.initials: KM
authors.lastname: Wasan
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000666:Amphotericin B / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000097:blood; D001835:Body Weight / Q000502:physiology; D006801:Humans; D008081:Liposomes / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D051381:Rats; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution / Q000502:physiology*
chemical_list: D000935:Antifungal Agents; D008081:Liposomes; C068538:liposomal amphotericin B; D000666:Amphotericin B