Drug Criteria & Outcomes: Lipid-based amphotericin B products formulary evaluation
By Brad Gilchrist, PharmD
Huntsville Hospital, Huntsville, AL
Lipid-based amphotericin B products compared
- Amphotericin B lipid complex (ABLC, Abelcet) — The Liposome Co.
- Amphotericin B colloidal dispersion (ABCD, Amphotec) — Sequus Pharmaceuticals
- Liposomal Amphotericin B (L-AmB, AmBisome) — Fujisawa
Background
Amphotericin B has a broad antifungal spectrum of activity, but poor patient tolerance and the potential for serious renal toxicity with prolonged use have limited its clinical utility. Common side effects of amphotericin B therapy are chills and fever (infusion-related), anemia, and nephrotoxic effects. Over the past 10 years, research has been done to improve the side effect profile of amphotericin B. This work has focused mainly on the delivery of amphotericin B to the site of infection. It is hoped that by developing a delivery system that limits exposure of the antifungal agent to host cells while achieving therapeutic levels of drug at the site of infection, a significant decrease in adverse effects such as renal toxicity can be achieved.
Pharmacology
Amphotericin B binds to ergosterol in the fungal cell membrane. This binding results in altered membrane permeability, leakage of essential cell contents, and cell death. The toxicity to mammalian cells is due to amphotericin B’s propensity to bind cholesterol.
Lipid-based amphotericin B products are believed to be less toxic to host cells compared to the conventional product. The pharmacological change, which underlies use of the new agents, is that incorporation of amphotericin B into a nontoxic carrier vehicle can protect host cells and ensure delivery of active drug to the site of infection.
It is believed that lipid products carry the drug preferentially to specific sites in the body such as the liver, lungs, and spleen, which are rich in reticuloendothelial system tissue, rather than renal tissue. In theory, these products should reach a lower concentration in renal tissues, thus resulting in a lower incidence of renal toxicity as compared to the conventional product.
Pharmacokinetics
Pharmacokinetic data are summarized in Table 1.
Indications and dosage
• Amphotericin B Lipid Complex (ABLC) — Indicated for all invasive fungal infections in patients for whom conventional amphotericin B (CAB) is unacceptable due to renal impairment or other toxicity, or in whom CAB has failed.
The recommended dosage of ABLC is 5 mg/kg/d IV in both adults and children.
• Amphotericin B Colloidal Dispersion (ABCD) — Indicated for invasive aspergillosis infections in patients for whom CAB is unacceptable due to renal impairment or other toxicity, or in whom CAB has failed.
The recommended initial dosage of ABCD is 3-4 mg/kg/d IV in adults and children. If there is no improvement or the disease progresses, the dose may be increased to 6 mg/kg/d. Dosages up to 8 mg/kg/d have been used.
• Liposomal amphotericin B (L-AmB) — Indicated for use in patients whose renal impairment or toxicity precludes the use of CAB. Indicated as initial intervention in empiric therapy in cases of presumed fungal infections in febrile neutropenic patients and in the treatment of visceral leishmaniasis.
Recommended dosage:
— For empiric treatment of fungal infections: 3 mg/kg/d.
— For visceral leishmaniasis in immunocompetent patients: 3 mg/kg/d on days 1-5 and on days 14 and 21.
— For visceral leishmaniasis in immunocompromised patients: 4 mg/kg/d on days 1-5 and on days 10, 17, 24, 31, and 38.
— For invasive fungal infections: 3-5 mg/kg/d depending on response and toxicity.
• Conventional amphotericin B (CAB) — Amphotericin B is effective for the treatment of serious infections due to Cryptococcus neoformans, Candida albicans, Histoplasma capsulatum, Coccidioides immitis, and Aspergillus fumigatus.
Usual doses range from 0.25 to 1.0 mg/kg/d for patients with normal renal function. The total daily dose should not exceed 1.5 mg/kg/d.
Common adverse effects
The most common adverse effects for the lipid-based amphotericin B products are the same as those seen with CAB, except to a lesser degree. These adverse effects include: infusion-related reactions such as chills/rigors, nausea, vomiting, hypertension, tachycardia, dyspnea, and hypoxia. Other effects including nephrotoxicity, sepsis, diarrhea, headache, thrombocytopenia, hypotension, abdominal pain, anemia, hyperbilirubinemia, hypokalemia, rash, chest pain, infection, gastrointestinal hemorrhage, increase in liver function tests, and leukopenia. Adverse effect rates for ABLC, ABCD, and L-AmB can be found in Table 2.
Clinical studies
• ABLC: Linden et al examined the relationship between dosage and therapeutic response of amphotericin B lipid complex by analyzing underlying diseases, types of infections, and therapeutic outcomes with different dosages as second-line antifungal therapy.1
This was a retrospective study that analyzed low-dose ABLC from three open-label, clinical, second-line treatment trials. Of the 555 patients enrolled (five enrolled twice) with invasive fungal infections, 289 failed and 267 were intolerant to conventional antifungal therapy.
Efficacy and safety data are presented in Tables 3 and 4.
This trial did not originally intend to differentiate between two doses of ABLC. The original protocol was for all patients to receive 5 mg/kg/d, but the physicians had flexible guidelines with regard to dosing and some patients received < 3 mg/kg/d. This study did show that ABLC does have efficacy in regard to the treatment of invasive fungal infections, but the 5 mg/kg/d dosage is still the recommended dose.
An article published in Clinical Infectious Disease in 1996 examined the safety and efficacy of ABLC as compared to CAB in the treatment of cryptococcal meningitis in patients with AIDS.2
This randomized trial included 55 patients who were assigned to receive six weeks of therapy with ABLC or CAB. Patients in the ABLC group (n = 38) were divided into three cohorts based on the dose. Twenty-one patients received the recommended dosage of 5 mg/kg/d.
Efficacy data can be found in Table 5, below.
There was no significant difference between infusion-related adverse events in the two groups. Statistically significant differences in the mean changes of serum creatinine and hemoglobin values from baseline favored patients who received ABLC 5 mg/ kg/d as compared to those receiving CAB. Hypokalemia and hypomagnesemia occurred in similar percentages in the ABLC 5 mg/kg/d group and the CAB group.
This trial had many limitations. The treatment groups produced by randomization were dissimilar in several aspects. Significantly more ABLC recipients than CAB recipients had three of four baseline characteristics that have been shown in prior studies to predict treatment failure. Also, the study design included treatment groups of insufficient size to give significant differences in efficacy.
The authors concluded that ABLC is an effective and less toxic alternative to CAB in the treatment of cryptococcal meningitis in patients with AIDS. The authors did point out that further study is needed.
• ABCD: White et al retrospectively compared 82 patients with proven or probable aspergillosis with 261 patients who received amphotericin B.3
Enrollment criteria included:
— failure of fungal infection to respond to amphotericin B treatment, defined as receipt of at least 15 mg/kg of amphotericin B without clinical improvement and extension of existing lesions or development of a new focus of infection, or use of amphotericin B for at least seven days without clinical improvement, and/or microbiological studies remaining positive for fungi;
— nephrotoxicity, defined as a doubling of serum creatinine or an increase of > 1.5 mg/dL from the pretreatment level;
— pre-existing renal impairment, defined as a serum creatinine of > 2.0 mg/dL;
— development of an invasive fungal infection after bone marrow transplantation and willingness to participate in a dose-escalating trial with ABCD.
A complete response was defined as resolution of all radiographic evidence of infection and the disappearance of all clinical signs of aspergillosis. A partial response was defined as clinical improvement with partial clearing of infection or stabilization of findings on relevant radiographic tests.
The development of renal toxicity during treatment was defined as a doubling of the serum creatinine level from baseline, an increase in the serum creatinine level of at least 1 mg/dL, or a 50% decrease in the calculated CrCl.
The dose of ABCD given ranged from 2.0 to 6.0 mg/kg. More dosing information is available in Table 6.
Of patients who received ABCD therapy, 23% received it because of failure to respond to amphotericin B, 32% because of nephrotoxic effects during amphotericin B therapy, 13% because of pre-existing renal impairment, and 32% because of enrollment in a dose-escalating trial.
Only limited information was presented about efficacy of treatment (see Table 7); there was no breakdown of how the different doses correlated with outcome.
Renal toxicity developed during treatment in 43.1% of amphotericin B patients compared with 8.2% of ABCD patients. No breakdown was given concerning dose and adverse experiences.
This study concluded that ABCD does appear to be a safe and efficacious alternative to CAB in the treatment of aspergillosis. This study had several limitations, including the fact that it was a retrospective, unblinded study comparing two different populations of patients. In the ABCD group, 85.4% of patients had received recent treatment with CAB. This could have had some effect on safety as well as efficacy. A true randomized, controlled trial is needed to support the role of ABCD as primary therapy for aspergillosis.
A study by Oppenheim et al enrolled 168 patients that exhibited one of the following characteristics:4
— responded incompletely to at least seven days of treatment with CAB;
— had experienced CAB-induced nephrotoxic effects;
— had pre-existing renal impairment;
— had experienced other CAB-related, treatment-limiting toxic effects.
Patients, depending on severity of infection and the investigator’s judgment, were given dosages initially of 0.5, 1.0, 2.0, 3.0, or 4.0 mg/ kg/d but were increased as required up to 6 mg/kg/d.
Ninety-seven of the 168 enrolled patients were available for clinical evaluation. Of these patients, 48 (49%) exhibited a favorable response to treatment. Reasons for exclusion from evaluation were as follows: insufficient documentation of fungal infection, administration of less than four doses of ABCD, concomitant administration of itraconazole, and investigator judgment.
Fourteen (8%) of the 168 patients withdrew from the study. Eleven of these patients withdrew due to chills, fever, and hypotension that may have been related to ABCD infusion. The other three patients exhibited elevated bilirubin or serum creatinine levels, which led to withdrawal. Sixty-four patients (38%) experienced infusion-related chills. Fever occurred in 44 patients (26%).
Seventeen of 126 patients (14%) who entered the trial with SCr £ 2.5 mg/dL had final SCr ³ 2.5 mg/dL. Thirty-nine of 124 patients (32%) had elevated transaminase levels at the end of treatment. Of the 39, 24 patients had elevated aspartate aminotransferase at enrollment.
This study provided evidence that ABCD is a viable alternative for patients intolerant or unresponsive to amphotericin B in the treatment of invasive mycoses. ABCD had favorable effects on renal function as compared to the data available on CAB. This study proved that ABCD should be considered for second-line treatment for invasive fungal infections.
• L-AmB. A randomized, double-blind, multicenter trial by Walsh et al included 687 patients who were febrile despite receiving at least 96 hours of broad-spectrum antibacterial therapy.5
— 343 patients were randomized to receive liposomal amphotericin B at a dose of 3.0 mg/kg/d. Investigators were permitted to increase the dose to a maximum of 6 mg/kg/d if deemed necessary.
— 344 patients were randomized to receive CAB at a dose of 0.6 mg/kg/ d. Investigators were permitted to increase this dose to a maximum of 1.2 mg/kg/d if deemed necessary.
All baseline categories were similar. Success was determined by five criteria: 1) survival for seven days after initiation of the study drug; 2) resolution of fever during the period of neutropenia; 3) successful treatment of any baseline fungal infection, if present; 4) absence of breakthrough fungal infections during administration of the study drug or within seven days after the completion of treatment; and 5) absence of premature discontinuation of the study drug because of toxicity or lack of efficacy.
The mean daily doses throughout the study were 3.0 ± 0.9 mg/kg/d for liposomal amphotericin B and 0.6 ± 0.2 mg/kg/d for CAB. The average duration of therapy was 10.8 days for liposomal amphotericin B and 10.3 for CAB.
This study proved the efficacy and safety of liposomal amphotericin B as compared to the conventional product. This study compared these two products for empiric therapy in neutropenic patients. The two products had similar efficacy, but the liposomal product had a better adverse effect profile. This study appears to have established liposomal amphotericin B as an appropriate alternative in patients who are intolerant of CAB therapy. Study results are summarized in Table 8.
Comparison of lipid-based products
• ABLC vs. L-AmB. Cannon et al performed a prospective and retrospective observational study set in an urban 350-bed teaching hospital.6 The patient population included 67 nonhemodialysis patients who were prescribed ABLC or L-AmB for more than three days.
The reason for the initiation of lipid-based formulations was assessed for all patients and found to be similar between the two treatment groups. These reasons included the following patient characteristics: 1) refractory to a prior course of antifungal therapy; 2) intolerant to prior antifungal therapy; 3) underlying renal dysfunction; 4) receipt of lipid-based therapy before hospitalization; and 5) lipid-based therapy chosen as first-line treatment.
The rationale for antifungal therapy was significantly different between ABLC and L-AmB (P < 0.044). ABLC was prescribed most frequently for documented fungal infections (50%), followed by neutropenic fever (33%). L-AmB was used more for neutropenic fever (62%), followed by the treatment of documented fungal infections (29%).
Forty-six patients (69%) received ABLC, while 21 patients (31%) received L-AmB. Patient demographics, dosage, and duration of ABLC and L-AmB, and underlying conditions were similar in both groups. Baseline serum creatinine was significantly higher in patients receiving ABLC as compared to those receiving L-AmB (1.77 vs. 1.0, P = 0.003).
Nephrotoxicity was defined as the increase of serum creatinine levels of 100% or more over pretreatment levels. In the ABLC group, two patients developed nephrotoxicity, while four patients in the L-AmB group developed nephrotoxicity.
Efficacy was based on the clinical response of patients with documented fungal isolates at the end of therapy. Clinical response was graded as complete response, partial response, or deterioration. Of patients with documented fungal infection, 20 of 23 patients (87%) treated with ABLC and four of five patients (80%) treated with L-AmB had a complete or partial response to therapy (no significant difference).
The authors concluded that there was no significant difference in nephrotoxicity or efficacy between the two products. They also concluded that until future studies show a clinically significant difference in nephrotoxicity between the products, economics should continue to be the major determinant for product selection.
Wingard et al conducted a randomized, double-blind comparative trial involving 244 neutropenic patients with unresolved fever after 72 hours of broad-spectrum antibiotic therapy.7
Patients were randomized to receive ABLC 5 mg/kg/d, L-AmB 3 mg/kg/d, or L-AmB 5 mg/ kg/d. The main focus of this trial was comparing frequency of chills/rigors and other infusion-related reactions, frequency of nephrotoxicity, and other safety parameters of the two lipid products.
Patients were deemed ineligible if their serum creatinine was ³ 3.0, or if they had uncontrolled bacteremia, had received more than two doses of CAB, had liver disease, or had an anticipated survival of two weeks or less. Administration of premeds prior to the first administration of medication was prohibited. After day 1, premedication was allowed. Saline loading was not standardized between patients.
According to the protocol, therapy was continued until the patient recovered from neutropenia or for up to three days after neutrophil recovery, up to a maximum of 42 days.
On day 1, infusion-related reactions occurred significantly less frequently in patients who received L-AmB compared to ABLC. After day 1, premedication was allowed before each infusion. The frequency of infusion-related reactions was reduced in the ABLC group, but remained the same in the two L-AmB groups. The difference was significant between the ABLC group and the 5 mg/kg L-AmB group. Also, the proportion of patients needing medication for infusion-related reactions following day 1 was not significant between any of the groups.
Nephrotoxicity, defined as an increase in serum creatinine value of more than 100% (if older than age 16, SCr must be > 1.2 at post-baseline serum creatinine), was significantly increased in the ABLC group as compared to the 5 mg/kg L-AmB group (P < 0.01). Nephrotoxicity was not significantly different between ABLC and the other L-AmB group. Overall, the average increase in serum creatinine between the three groups was 0.2-0.7 mg/dL.
There were no significant differences between the groups in terms of hepatotoxicity, hypokalemia, and anemia. Other than infusion-related effects and nephrotoxicity, the only significant difference was the increase in hypoxia in the ABLC group as compared to the 5 mg/kg L-AmB group.
There was no statistically significant difference in response between the three groups.
The authors concluded that L-AmB was associated with significantly less nephrotoxicity and significantly fewer infusion-related reactions than ABLC. There were several limitations to this study that need to be addressed. In terms of the data on infusion-related reactions, there were no premeds given on the first day of therapy, which is common practice for either agent. After the first day of therapy, premeds were allowed, and the incidence of infusion-related reactions trended downward in the ABLC group. The analysis of nephrotoxicity examined peak serum creatinine values rather than comparing baseline and end-of-therapy values like most other studies.
Pharmacoeconomics
Pharmacoeconomic data are presented in Table 9 and Table 10. provides a cost analysis example of a 72 kg patient with an invasive fungal infection.
Recommendations
The lipid-based amphotericin B products have been proven in clinical trials to be safer than and as efficacious as the CAB product. The three products available at this time — ABLC (Abelcet), ABCD (Amphotec), and L-AmB (AmBisome) — must distinguish themselves from one another based on adverse effect profile and cost.
The safety and efficacy of ABLC and L-AmB have been studied in two trials. ABCD has yet to be compared to the other two products in a formalized trial. In clinical trials, all three products have been shown to be safer than and as efficacious as conventional amphotericin B.
In choosing a formulary agent, the available literature comparing the products must be examined. With no comparative literature on ABCD, it is not a suitable choice as the formulary agent.
After evaluation of the trials comparing ABLC and L-AmB, there appears to be little difference between these agents in terms of safety and efficacy. Recent data show that there could be a decreased incidence of infusion-related reactions with L-AmB as compared to ABLC. This incidence can be minimized by using premeds prior to infusion. In terms of nephrotoxicity, it appears that the rate of nephrotoxicity is similar. In one of the comparative trials it did appear that L-AmB was associated with less nephrotoxicity. Due to limitations of this study, a judgment based on nephrotoxicity would be suitable when more information regarding these agents is available.
ABLC currently is the lipid-based product used in Huntsville Hospital. It is used even more than CAB. Currently available data prove that all of the lipid-based products have similar safety and efficacy. With only two trials comparing ABLC and L-AmB, there are limited data on which to make a formulary decision. The cost of ABLC is considerably less than that of L-AmB; until further comparative trials prove otherwise, formulary decisions should be based on economics.
Cost is a very important consideration when choosing whether to use a lipid-based amphotericin B product. The cost of a lipid-based product is hundreds of dollars a day. The drug cost of a day of treatment with the conventional product would cost just a few dollars. Thus, strict criteria need to be developed regarding the use of the lipid-based products.
Indications for the use of a lipid-based amphotericin B product are as follows:
— Treatment of susceptible fungal infections in patients with poor renal function (SCr ³ 2.5 mg/dL in adults or ³ 1.5 mg/dL in children, or an estimated CrCl of £ 25 mL/min) who are either refractory to or inappropriate candidates for itraconazole or fluconazole therapy.
— Patients who are either refractory to or inappropriate candidates for itraconazole or fluconazole therapy and have developed nephrotoxicity prior to or while receiving conventional amphotericin B (SCr increase to ³ 2.5 mg/dL in adults or ³ 1.5 mg/dL in children, doubling of SCr, or estimated CrCl of £ 25 mL/min).
— Infusion-related toxicities that persist seven days after initiation of conventional amphotericin B, despite use of pretreatments before infusion, or significant hypotension (drop in systolic blood pressure of 40 mmHg and/or a drop in diastolic blood pressure of 20 mmHg).
— Patients with end-stage renal disease requiring hemodialysis should not receive amphotericin B lipid products unless one of the above indications apply. Patients undergoing peritoneal dialysis should be regarded as candidates for lipid-based therapy because they do have some kidney function remaining.
— Patients with invasive mold infection (i.e., aspergillus, mucor, fusarium).
References
1. Linden P, et al. Retrospective analysis of the dosage of amphotericin B lipid complex for the treatment of invasive fungal infections. Pharmacotherapy 1999; 19:1261-1268.
2. Sharkey P, et al. Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 1996; 22:315-321.
3. White M, et al. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis 1997; 24:635-642.
4. Oppenheim B, et al. The safety and efficacy of amphotericin B colloidal dispersion in the treatment of invasive mycoses. Clin Infect Dis 1995; 21:1145-1153.
5. Walsh T, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999; 340:764-771.
6. Cannon J, et al. A prospective and retrospective analysis of the nephrotoxicity and efficacy of lipid-based amphotericin B formulations. Pharmacotherapy 2001; 21:1107-1114.
7. Wingard J, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clin Infect Dis 2000; 31:1155-1163.
Additional Resources
• "Amphotericin B Lipid Products (Abelcet and AmBisome) — Guidelines for Use." College Park, MD: University of Maryland Medical Center; August 2000.
• Como J, ed. Lipid-based amphotericin B products — a restrained approach. Drug Information Bull 1999; 33:1-4.
• Como J, ed. P & T reviews lipid-based amphotericin B products: Guidelines for use developed. Drug Information Bull 1999; 33:1-6.
• Dismukes W. Introduction to antifungal drugs. Clin Infect Dis 2000; 30:653-657.
• Kaltenbach B, Ross M. Review of the lipid-based amphotericin B products. Pharmacol Ther 1998; September: 487-494.
• Micromedex Healthcare Series. Englewood, CO: MICROMEDEX Inc.; 2000.
• Product Information: Abelcet, amphotericin B lipid complex. Princeton, NJ: The Liposome Company, Inc.; 1996.
• Product Information: AmBisome, amphotericin B liposome. Deerfield, IL: Fujisawa USA, Inc.; 1997
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