Cochleate Amphotericin B: Pharmacokinetic studies in animal studies

Kalbag S 1, Ahl P 1, Lu R 1, Machado H 1, Marone P 1, Ngoje J 1, Finn A 2, Delmas G 3, Perlin D 3, Mannino R 1

Author address: 

1 BioDelivery Sciences International, Inc., Newark, USA, 2 BioDelivery Sciences International, Inc., Morrisville, USA, 3 Public Health Research Institute, Newark, USA


Cochleates are stable particles comprised of naturally occurring phospholipids such as phosphatidylserine (PS) and calcium. Their multilayered structure has been shown to stabilize biomolecules and pharmaceuticals against hazardous environmental conditions, enzymatic degradation, and permits lyophilized preparations without structural change and loss of activity. Cochleate Amphotericin B (CAMB) has shown excellent activity and low toxicity in murine models of disseminated aspergillosis and disseminated candidiasis. Previously we have reported on the successful scaling up of CAMB suspension preparations (soy PS: AmB, 5:1) whose stability was improved in the presence of methyl cellulose and parabens. In this study we report the pharmacokinetics (PK) following oral delivery of CAMB in a murine model of candidiasis and in healthy rats and dogs in 7-day repeat dosing studies. Mice challenged with Candida albicans (1X 105 cfu, tail vein) were dosed daily for 14 days with CAMB orally and Amphotericin B with deoxycholate (DAMB) intraperitoneally. At various times, blood was collected from mice, animals sacrificed, and liver, lung, and kidney tissues were harvested. Plasma and tissue amphotericin B (AmB) was quantitated. In the 7-day studies, male Sprague Dawley rats (N=5) and male Beagle dogs (N=3) were dosed once daily with DAMB, 0.5 mg/kg IV by infusion over 30 min and CAMB orally (10 and 30 mg/kg). On Day 7 postdose, blood was taken at 10 timepoints over 24 hours (for IV dosing) and 36-48 hours (for PO dosing). Pre-dose sampling was done on Days 1-7. Rats were sacrificed and tissues harvested were either frozen for AmB quantitation or fixed for histopathology. Quantitative levels of plasma AmB were observed in mice, rats, and dogs following oral dosing using RP-HPLC analysis with UV detection. Mouse tissue analysis showed quantitative levels of AmB in all tissues while rat tissue analysis is ongoing. AUC, Cmax and Tmax values were determined for all groups in the rat and dog studies. In addition, an IV formulation of CAMB is also being developed using dioleoyl phosphatidyl serine (DOPS) and AmB (5:1). The formulation contained 0.1% rabbit serum albumin and 0.9% saline but no methyl cellulose or parabens. Particle size analysis revealed all particles to be

abstract No: 


Full conference title: 

15th Annual Focus on Fungal Infections
    • FFI 15th (2005)