Dose-response relationships of three amphotericin B formulations in a non-neutropenic murine model of invasive aspergillosis

Abstract

New lipid-associated formulations of amphotericin B (AmB) have been developed in order to reduce toxicity and enhance the efficacy of AmB by allowing administration of higher doses of the drug. We determined the in vivo dose-response relationships of 1 day and 7 day treatment of AmB, Ambisome (AmBi) and Abelcet (ABLC) in a non-neutropenic murine model of invasive aspergillosis by using survival as an endpoint. Female CD-1 mice were infected intravenously 48 h prior to start therapy with Aspergillus fumigatus (1×10⁷ conidia/mouse). Groups of 10 mice were treated iv for 1 day or 7 days with increasing 2-fold doses of AmB, ABLC and AmBi up to a maximum of 20 mg/kg/day. Mortality was determined twice daily until day 15. Results were analyzed using product-moment survival analysis and by determining the dose response relationships on day 15. Survival at day 15 of mice with 7 day AmBi or ABLC treatment was significantly better than that of controls or AmB. The ED50s of AmBi and ABLC were 0.06 (95% CI: 0.03–0.127) mg/kg and 0.21 (0.06–0.66) mg/kg respectively. In addition, the maximum effect was higher for AmBi than ABLC, 90% survival versus 68%, respectively. Most of the effects of treatment with AmBi were reached after 1 day of treatment, indicating that the first dose given is most important in predicting survival. This study shows that AmBi and ABLC were significantly more efficacious than AmB in a non-neutropenic murine model of invasive aspergillosis, and that the effect observed was primarily dependent on the first dose administered.

Keywords:

• Aspergillus
• amphotericin B
• animal model

Acknowledgements

This study was supported by unrestricted grants from Gilead, Inc. and Wyeth Inc., NL.

Disclosure of conflicts of interest

JFM is/was consultant for Zeneus Pharma, Pfizer and Merck. JWM is/was consultant and/or member of advisory boards for Astellas, Basilea, Merck, Pfizer and Wyeth Inc. PEV is/was consultant for Merck and Pfizer, has received research grants from Cephalon, Schering-Plough, Pfizer, Merck, Basilea and is on the Speaker's bureau of Gilead, Merck, and Schering-Plough.