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JAC Advance Access published online on February 19, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn048
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

In vivo distribution and therapeutic efficacy of a novel amphotericin B poly-aggregated formulation

R. Espada1, S. Valdespina1, M. A. Dea2, G. Molero3, M. P. Ballesteros1, F. Bolás2 and J. J. Torrado1,*

1 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain 2 Department of Parasitology, Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain 3 Department of Microbiology, Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain

Received 25 September 2007; returned 11 January 2008; revised 8 January 2008; accepted 21 January 2008

* Corresponding author. Tel: +34-913941620; Fax: +34-913941736; E-mail: torrado1{at}farm.ucm.es

Objectives: The purpose of this investigation is the study of toxicity, in vivo distribution and therapeutic activity against candidiasis of poly-aggregated amphotericin B, in two different formulations: not microencapsulated (P-AMB) or incorporated in albumin microspheres (MP-AMB).

Methods: The therapeutic efficacy and toxicity of amphotericin B formulations was studied in an immunocompetent murine model of systemic candidiasis. A pharmacokinetic study was also performed to measure the plasma, kidney, liver and spleen amphotericin B concentrations after administration of the three formulations to mice.

Results: The acute toxicity of P-AMB in mice is lower than that of the conventional amphotericin B reference formulation (D-AMB). The 50% lethal doses were increased at least eight times. Intravenous bolus administration of doses up to 40 mg/kg of body weight of poly-aggregated amphotericin B, either P-AMB or MP-AMB, did not produce acute symptoms of toxicity. Interestingly, in the pharmacokinetic study, significant (P < 0.05) lower plasma and kidney amphotericin B concentrations and higher liver and spleen amphotericin B concentrations were achieved after poly-aggregated amphotericin B formulation (P-AMB and MP-AMB) administration in relation to the reference formulation (D-AMB). At high amphotericin B doses, no significant differences in efficacy (P > 0.05) were observed among the formulations (D-AMB, P-AMB and MP-AMB).

Conclusions: Although the efficacy in the candidiasis treatment was decreased as a consequence of amphotericin B aggregation, it can be compensated by the possibility of increasing the doses with lower nephrotoxicity. Moreover, due to its lower toxicity while maintaining its effectiveness, the poly-aggregated formulations (P-AMB and MP-AMB) have a better therapeutic index than the conventional formulation (D-AMB).

Key Words: aggregation state , candidiasis , therapeutic index , toxicity


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