Application of Physiologically Based Pharmacokinetic Model to Compare the Biodistribution of Liposomal Amphotericin B With Conventional Amphotericin B Deoxycholate in Humans

ABSTRACT Amphotericin B (AmB) has been a cornerstone in the treatment of invasive fungal infections for over 6 decades. Compared with conventional amphotericin B deoxycholate (AmB‐DOC), liposomal amphotericin B has comparable efficacy but less nephrotoxicity. The main purpose of this study was to investigate the reason why liposomal amphotericin B has similar therapeutic effects but lower toxicity and the differences of distribution in humans between liposomal amphotericin B and AmB‐DOC. To compare the distribution of liposomal amphotericin B and AmB‐DOC in humans, the physiologically based pharmacokinetic (PBPK) model was established by bottom‐up stepwise method. A rat PBPK model was established firstly, then verified in mouse level in consideration of interspecies differences in physiological‐ and drug‐specific parameters, and finally the PBPK model was extrapolated to humans. Based on preclinical and clinical pharmacokinetic (PK) studies, the AmB‐DOC and liposomal amphotericin B PBPK model were established, respectively. The simulated results of human PBPK model showed that the liposomal formulation changed the pharmacokinetic characteristics of AmB. Compared with AmB‐DOC, the plasma exposure of liposomal formulation was higher, but the renal exposure was significantly reduced.