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

Abstract

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).

• Authors: R Espada, S Valdespina, M A Dea, G Molero, M P Ballesteros, F Bolás, J J Torrado
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 61 Issue 5 Pg. 1125-31 (May 2008) ISSN: 1460-2091 [Electronic] England
• PMID: 18285313 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Dosage Forms
• Amphotericin B

Topics

• Amphotericin B (adverse effects, blood, chemistry, pharmacokinetics, therapeutic use)
• Animals
• Antifungal Agents (adverse effects, blood, chemistry, pharmacokinetics, therapeutic use)
• Candidiasis (drug therapy)
• Dosage Forms
• Dose-Response Relationship, Drug
• Hot Temperature
• Kidney (drug effects, microbiology, pathology)
• Liver (chemistry)
• Mice
• Mice, Inbred ICR
• Spleen (chemistry)
• Tissue Distribution