In vivo distribution and therapeutic efficacy of a novel amphotericin B poly-aggregated formulation.
OBJECTIVE
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).
Espada
R
R
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University, 28040 Madrid, Spain.
Valdespina
S
S
Dea
M A
MA
Molero
G
G
Ballesteros
M P
MP
Bolás
F
F
Torrado
J J
JJ
D000666:Amphotericin B / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002177:Candidiasis / Q000188:drug therapy*; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D007668:Kidney / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008099:Liver / Q000737:chemistry; D051379:Mice; D008813:Mice, Inbred ICR; D013154:Spleen / Q000737:chemistry; D014018:Tissue Distribution
D000935:Antifungal Agents; D004304:Dosage Forms; D000666:Amphotericin B