Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Background: Delivery of monomeric Amphotericin B (AmB), i.e. deaggregated AmB, has been a major tactic in the reduction of renal toxicity at a membrane level, taking advantage of the selectivity of monomeric AmB for binding ergosterol over cholesterol. Objective: The aim of this study was to characterize the pharmacokinetic (PK) and renal toxicity of monomeric AmB in rats following a multiple dose regimen. Method: AmB existed primarily in a monomeric state in poly(ethylene glycol)-block-poly(N-hexyl stearate Laspartamide) (PEG-b-PHSA) micelles (mAmB) at 2:1 ratio (mol:mol), whereas AmB as its standard formulation, Fungizone®, was highly self-aggregated based on absorption spectroscopy. Results: After single intravenous injection, mAmB significantly (p < 0.001) increased the area under the plasma drug concentration-time curve (AUC) and reduced the volume of distribution (Vd) and total systemic clearance (CL) relative to Fungizone®. After daily intravenous injections at dose of 1.0 mg/kg for 7 days, PK parameters of mAmB and Fungizone® were similar to day 1. The treatment of Fungizone® also significantly (p < 0.05) increased levels of urinary enzymes, N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) by 3.1- and 3.0 fold, respectively, whereas levels of NAG and KIM-1 were unchanged for mAmB, consistent with hematoxylin and eosin (H) staining of excised kidneys. Conclusion: In summary, mAmB causes less renal toxicity than AmB as Fungizone® in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmB in vivo.