A Prospective and Retrospective Analysis of the Nephrotoxicity and Efficacy of Lipid-Based Amphotericin B Formulations

Joan P. Cannon, Pharm.D., Kevin W. Garey, Pharm.D., and Larry H. Danziger, Pharm.D.

Disclosures

Pharmacotherapy. 2001;21(9) 

In This Article

Abstract and Introduction

Study Objective. To determine the usage patterns of the lipid-based amphotericin B formulations at our institution and to compare the observed nephrotoxicity and efficacy of these formulations.
Design. Prospective and retrospective observational study.
Setting. Urban 350-bed teaching hospital.
Patients. Sixty-seven nonhemodialysis patients who were prescribed greater than 3 days of amphotericin B lipid complex (ABLC) or liposomal amphotericin B (L-AmB) from 1996-1999.
Measurements and Results. Forty-six patients received ABLC and 21 received L-AmB. Oncology patients accounted for most prescriptions of both formulations. Amphotericin B lipid complex most frequently was prescribed for treatment of documented fungal infections (50%), followed by treatment of neutropenic fever (33%). Liposomal amphotericin B most frequently was prescribed for treatment of neutropenic fever (62%), followed by treatment of documented fungal infections (29%). Seventy-eight percent of patients treated with ABLC and 90% of those who received L-AmB were started on the lipid-based formulation due to being refractory or intolerant to prior antifungal therapy. Two (4.4%) patients receiving ABLC and four (19%) patients receiving L-AmB experienced nephrotoxicity at the end of therapy (NS). Of the patients with a documented fungal infection, 20 out of 23 (87%) of those treated with ABLC and 4 out of 5 (80%) of those treated with L-AmB had a complete or partial response to therapy (NS). One patient with febrile neutropenia had a breakthrough fungal infection while receiving L-AmB.
Conclusion. No significant differences in nephrotoxicity or efficacy were found between ABLC and L-AmB. Until further studies indicate clinically significant differences in nephrotoxicity between the two liposomal amphotericin B formulations, it is recommended that economics continue to be the major determinant for product selection.

The frequency of invasive fungal infections has increased dramatically due to an increased number of immunocompromised patients secondary to oncology therapy and trans-plantation.[1,2] Between 1980 and 1990, the number of nosocomial Candida infections of blood, urine, and surgical wounds more than doubled, such that Candida species are now the fourth most common pathogen isolated from blood.[3] Autopsy reports showed an increase in invasive Aspergillus infections from 0.4% in the 1960s to 2-4% in the 1990s.[4,5,6] Furthermore, with the advent of the human immunodeficiency virus (HIV) epidemic, the frequency of cryptococcal disease increased more than 5-fold from the 1980s to the 1990s.[6]

The polyene antifungal agent amphotericin B deoxycholate has been the treatment of choice for invasive fungal infections since its introduction in the 1960s.[7] In vitro, it is characterized by rapid fungicidal activity; however, it is associated with many serious adverse effects, including nephrotoxicity. Since 1995, the Food and Drug Administration approved three lipid-based amphotericin B formulations: amphotericin B lipid complex (ABLC; Abelcet, The Liposome Company, Princeton, NJ), amphotericin colloidal dispersion (ABCD; Amphotec, Sequus Pharmaceuticals, Menlo Park, CA), and liposomal amphotericin B (L-AmB; AmBisome, Fujisawa Healthcare, Deerfield, IL). All of these newer formulations have a significantly decreased frequency of nephrotoxicity compared with amphotericin B deoxycholate and are indicated for treatment of patients refractory to or intolerant of amphotericin B deoxycholate.[8,9,10] In addition, L-AmB is indicated for the empirical therapy of presumed fungal infections in febrile neutropenic patients and for treatment of visceral leishmaniasis.[10] It is important to note that clinical studies of these agents employed different criteria to define nephrotoxicity, and no official definition of nephrotoxicity is established. In general, these studies used serum creatinine as the surrogate marker for renal function.

Differences in nephrotoxicity and efficacy among the various lipid-based formulations have not been well established. Most published studies either compared the lipid-based formulations against the "gold standard," amphotericin B deoxycholate, or did not include a comparator group. One study followed 556 patients with a variety of underlying conditions treated with ABLC.[11] A complete or partial response was reported in over 50% of the 291 patients with proven fungal infections. Nephrotoxicity was observed in 24% of all the patients.

Other researchers reported a cure or improve-ment in 53% of 59 evaluable patients who had undergone bone marrow transplant and had a documented fungal infection treated with ABLC.[12] In 38 mycologically evaluable patients in the study, fungal pathogens were eradicated in 50%. Only 3% of patients experienced nephrotoxicity.

Studies with L-AmB demonstrated similar results to those obtained with ABLC. One research group investigated neutropenic patients with documented or suspected fungal infections treated with L-AmB (30 patients) or ampho-tericin B deoxycholate (33 patients).[13] Patients treated with L-AmB had significantly better response rates (50% vs 24%) and less nephrotoxicity (12% vs 41%) than those treated with amphotericin B deoxycholate. Another research group studied 116 neutropenic patients with documented or suspected fungal infections treated with L-AmB in over 133 episodes of neutropenic fever.[14] A successful outcome was achieved in 61% of the patients, and no patients experienced renal deterioration.

Although the new lipid-based formulations share the common properties of decreased nephrotoxicity and equal or increased efficacy compared with amphotericin B deoxycholate, they have different pharmacokinetic characteristics. This has led to speculation that perhaps there are clinically significant differences among the formulations as well. Unfortunately, there is a paucity of data comparing the safety and efficacy of the lipid-based formulations.

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