Oral Dosing of Encochleated Amphotericin B (CAmB): Rapid Drug Targeting to Infected Tissues in Mice with Systemic Candidiasis

R. J. Mannino1, D. S. Perlin2;

Author address: 

1Rutgers New Jersey Med. Sch., Newark, NJ, 2Publ. Hlth. Res. Inst. Ctr., Newark, NJ

Abstract: 

Background: 

Amphotericin B (AmB), due to its fungicidal efficacy, broad spectrum and limited resistance, can be considered the “gold standard” antifungal treatment. However, use of AmB is limited by toxicity and intravenous administration. CAmB is a lipid-crystal, nano-particle formulation designed for targeted oral delivery of AmB to the infected tissue without the associated toxicity. 

Methods: 

BALB/c mice (N=65) were infected on Day 0 with 5 × 105cells of Candida albicans. After infection mice were treated for 14-days with control, DAmB (Amphotericin B deoxycholate) 2 mg/kg intraperitoneal, or CAmB 10 mg/kg oral. Untreated and uninfected mice were used as blank controls. Five mice from each treatment group were sacrificed on days 1, 3, 5, 7, 11, and 15. Plasma and tissues were collected for analysis of AmB concentrations. 

Results: 

Concentrations of AmB in plasma were undetectable in 61% of the CAmB and 44% of DAmB samples with no significant difference in plasma levels between groups. In the tissues however, quantifiable AmB levels were seen in all samples (See Figure), with CAmB reaching the MIC of 0.25 µg/ml in 1-2 days whereas DAmB takes 3-5 days to reach the MIC-level. At the efficacious dose, tissue levels levels for CAmB stay at 2-3x the MIC, whereas DAmB causes tissue levels to increase to 4-40x the MIC.

Conclusions: 

In Candida-infected mice, orally administered CAmB is taken up from the GI tract resulting in significant tissue concentrations above the MIC level. Contrary to DAmB, concentrations of AmB from CAmB accumulate rapidly in the tissues without escalating to extremely high levels during the second week of treatment, potentially mitigating side effects and toxicities.

abstract No: 

A-054
    • ICAAC 55th (2015)