Pharmacokinetics Characterization of Liposomal Amphotericin B: Investigation of Clearance Process and Drug Interaction Potential

Abstract

AmBisome, a liposomal formulation of amphotericin B (CAS 1397-89-3, L-AMB), shows different pharmacokinetics from the conventional formulation, amphotericin B deoxycholate (D-AMB). To characterize the clearance process of L-AMB, the form in which it exists in rat plasma, pharmacokinetics in hepatic or renal failure rats, cellular distribution in rat liver, and placental and milk transfer in rat were investigated. Furthermore, to predict the drug-drug interaction, in vitro metabolism of amphotericin B (AMB) by rat, dog and human liver S9 fraction, and effects of L-AMB on drug-metabolizing enzyme systems were investigated. L-AMB was found to exist stably as a liposomal form in rat plasma without any notable transfer to milk or fetus in rats. After administration to hepatic failure rats, the CLtot of AMB decreased to 1/4 and the Vdss decreased to 1/8 compared with the control rat case. In contrast, after administration to renal failure rats, plasma AUC of AMB did not significantly change compared with sham-operated rats. These data suggest that hepatic clearance is the main determinant of the CLtot for L-AMB. In rat liver, L-AMB was distributed mainly to non-parenchymal cells. In the in vitro metabolism study using liver S9 fraction, no metabolite peaks were observed. After repeated administration of L-AMB to rats, there was no change in parameters related to the drug-metabolising enzyme system in liver microsomes. These data demonstrate that clinically significant metabolism-based drug interaction with L-AMB should be less likely.

Amphotericin B Pharmacokinetics: Inter-strain Differences in Rats Following Intravenous Administration of the Most Commonly Marketed Formulations of the Drug

“…In the previous studies performed on other drugs ( 16 , 25 - 27 ), the PK differences between SD and Wistar rats have been typically attributed to metabolism variations, especially in the liver enzymes of these two rat strains. AmB has no known metabolism pathway and is dominantly excreted intact in feces ( 15 , 28 ), so this explanation is less likely in the case of AmB. As mentioned before, AmB has a very high protein binding ( 29 ).…”

“…For AmBisome, the drug molecules are predominantly encased in liposomes and are less available to bind to plasma proteins ( 2 , 15 ). Therefore, it is expected that the inter-strain variation in the amount of plasma protein will have less effect on the PK of liposomal form compared to Fungizone.…”

“…Scientists attempting to establish new drug delivery systems for AmB typically obtain the PK parameters of their developed system in rats, which are a suitable animal model for such studies, and compare their results with those reported for Fungizone and AmBisome. Looking at AmB PK data (Table 1) collected from previous reports (7)(8)(9)(10)(11)(12)(13)(14)(15), regardless of the type of formulation, AmBisome, or Fungizone, there are apparent differences between the results reported for the PK parameters of the drug. Due to the similarity of the medications and prescribed dosage, using different strains of rats in the previously reported studies may be an influential factor.…”

Physiologically Based Pharmacokinetic Model of Amphotericin B Disposition in Rats Following Administration of Deoxycholate Formulation (Fungizone®): Pooled Analysis of Published Data

“…The drug undergoes urinary and biliary excretion; however, these pathways account for less than 50% of elimination (10), and no metabolites have been identified (9,29). To capture the data, an additional elimination pathway had to be incorporated into the PBPK model.…”

“…The drug significantly binds to albumin, α1-acid glycoprotein and lipoproteins, with unusual nonlinear binding behavior reported in humans (8). No metabolic pathway has been identified for AmB (9), and biliary and metabolic clearances only account for 3-40% of total elimination, which is species dependent (10). AmB shows significant tissue distribution and prolonged tissue storage as evidenced by a high volume of distribution, slow rates of transfer from a peripheral compartment in comparison to rate of transfer to the peripheral compartment, as well as high tissue concentrations relative to plasma (11).…”