R P Rapp1, P O Gubbins, M E Evans. 1. College of Pharmacy, University of Kentucky Medical Center, Lexington, USA.
Abstract
OBJECTIVE: To evaluate the published data on the effectiveness and safety of amphotericin B lipid complex (ABLC) for the treatment of invasive mycosis and to evaluate data describing the pharmacologic properties and pharmacokinetic behavior of ABLC in both animals and humans. DATA SOURCE: A MEDLINE search was conducted to identify literature published from 1965 to January 1997 for amphotericin B deoxycholate (DCAB) and ABLC. In addition, preliminary data published as abstracts and presented at national conferences on infectious disease and hematology within the last 6 years were also included in this review. STUDY SELECTION: Both human and animal studies were reviewed. Animal and in vitro studies were selected to evaluate the pharmacologic and toxicologic properties of ABLC. For the evaluation of the efficacy, safety, and pharmacokinetic behavior of ABLC, large, well-controlled studies were reviewed. In addition, data from open-label and emergency use protocols were also included in the review. DATA EXTRACTION: The study and analytical methods, results, and conclusions of the selected studies were evaluated. Pharmacokinetic data for both ABLC and DCAB that were derived from human subjects were also evaluated. DATA SYNTHESIS: DCAB has been the cornerstone for the treatment of invasive mycosis, even though it has a narrow therapeutic index. Infusion-related toxicities (e.g., fever, chills, rigors) are likely due to DCAB stimulation of cytokine and prostaglandin synthesis. Conversely, nephrotoxicity, the primary non-infusion-related toxicity, likely results from the nonselective cytotoxic interaction between DCAB and cholesterol-containing mammalian cells. ABLC represents a new approach to improving the therapeutic index of DCAB. Mammalian cytotoxicity is attenuated by complexing amphotericin B to a mixture of phospholipids. This alters the affinity of amphotericin B and decreases its selective transfer from the complex to cholesterol-containing mammalian cells. Fungi also possess lipase, which improves the selective transfer from the complex to ergosterol-containing cell membranes. In humans, the lipid formulation increases the volume of distribution of amphotericin B. Thus, compared with DCAB, larger doses of ABLC can be administered for a longer duration with less nephrotoxicity. However, the prevalence of infusion-related toxicities associated with ABLC is similar to that of DCAB. Whether the alteration in distribution improves efficacy by improving tissue concentrations of amphotericin B has not been determined. The cost of this agent will limit its use. CONCLUSIONS: ABLC has been shown to be at least as effective as DCAB, and it has been well tolerated in the clinical studies to date. Despite large dosages and extended courses of administration, there is little nephrotoxicity associated with its use. However, the cost of this agent will limit its use to the treatment of refractory mycosis or to cases where DCAB is contraindicated due to significant renal insufficiency.
OBJECTIVE: To evaluate the published data on the effectiveness and safety of amphotericin B lipid complex (ABLC) for the treatment of invasive mycosis and to evaluate data describing the pharmacologic properties and pharmacokinetic behavior of ABLC in both animals and humans. DATA SOURCE: A MEDLINE search was conducted to identify literature published from 1965 to January 1997 for amphotericin B deoxycholate (DCAB) and ABLC. In addition, preliminary data published as abstracts and presented at national conferences on infectious disease and hematology within the last 6 years were also included in this review. STUDY SELECTION: Both human and animal studies were reviewed. Animal and in vitro studies were selected to evaluate the pharmacologic and toxicologic properties of ABLC. For the evaluation of the efficacy, safety, and pharmacokinetic behavior of ABLC, large, well-controlled studies were reviewed. In addition, data from open-label and emergency use protocols were also included in the review. DATA EXTRACTION: The study and analytical methods, results, and conclusions of the selected studies were evaluated. Pharmacokinetic data for both ABLC and DCAB that were derived from human subjects were also evaluated. DATA SYNTHESIS: DCAB has been the cornerstone for the treatment of invasive mycosis, even though it has a narrow therapeutic index. Infusion-related toxicities (e.g., fever, chills, rigors) are likely due to DCAB stimulation of cytokine and prostaglandin synthesis. Conversely, nephrotoxicity, the primary non-infusion-related toxicity, likely results from the nonselective cytotoxic interaction between DCAB and cholesterol-containing mammalian cells. ABLC represents a new approach to improving the therapeutic index of DCAB. Mammaliancytotoxicity is attenuated by complexing amphotericin B to a mixture of phospholipids. This alters the affinity of amphotericin B and decreases its selective transfer from the complex to cholesterol-containing mammalian cells. Fungi also possess lipase, which improves the selective transfer from the complex to ergosterol-containing cell membranes. In humans, the lipid formulation increases the volume of distribution of amphotericin B. Thus, compared with DCAB, larger doses of ABLC can be administered for a longer duration with less nephrotoxicity. However, the prevalence of infusion-related toxicities associated with ABLC is similar to that of DCAB. Whether the alteration in distribution improves efficacy by improving tissue concentrations of amphotericin B has not been determined. The cost of this agent will limit its use. CONCLUSIONS: ABLC has been shown to be at least as effective as DCAB, and it has been well tolerated in the clinical studies to date. Despite large dosages and extended courses of administration, there is little nephrotoxicity associated with its use. However, the cost of this agent will limit its use to the treatment of refractory mycosis or to cases where DCAB is contraindicated due to significant renal insufficiency.