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Antimicrobial Agents and Chemotherapy, September 1998, p. 2391-2398, Vol. 42, No. 9
Pediatric Oncology
Branch1 and
Medicine
Branch,8
National Cancer Institute,
Received 30 June 1997/Returned for modification 17 October
1997/Accepted 3 May 1998
The safety, tolerance, and pharmacokinetics of a small unilamellar
liposomal formulation of amphotericin B (AmBisome) administered for
empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and
bone marrow transplantation. The protocol was an open-label,
sequential-dose-escalation, multidose pharmacokinetic study which
enrolled a total of 8 to 12 patients in each of the four dosage
cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or
7.5 mg of amphotericin B in the form of AmBisome/kg of body
weight. The study population consisted of patients between the ages of
13 and 80 years with neutropenia (absolute neutrophil count,
<500/mm3) who were eligible to receive empirical
antifungal therapy. Patients were monitored for safety and tolerance by
frequent laboratory examinations and the monitoring of infusion-related
reactions. Efficacy was assessed by monitoring for the development of
invasive fungal infection. The pharmacokinetic parameters of
AmBisome were measured as those of amphotericin B by
high-performance liquid chromatography. Noncompartmental methods were
used to calculate pharmacokinetic parameters. AmBisome
administered as a 1-h infusion in this population was well tolerated
and was seldom associated with infusion-related toxicity.
Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum
creatinine, potassium, and magnesium levels were not significantly
changed from baseline in any of the dosage cohorts, and there was no
net increase in serum transaminase levels. AmBisome followed
a nonlinear dosage relationship that was consistent with
reticuloendothelial uptake and redistribution. There were no
breakthrough fungal infections during empirical therapy with
AmBisome. AmBisome administered to febrile
neutropenic patients in this study was well tolerated, was seldom
associated with infusion-related toxicity, was characterized by
nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.
Invasive fungal infections are
important causes of morbidity and mortality in neutropenic patients
(20, 22, 29). The use of conventional amphotericin B in
neutropenic patients may be compromised by dose-limiting toxicity and
infusion-related acute toxicity (8). Recently, advances have
been made in the development of lipid formulations of amphotericin B
which permit delivery of higher doses while sparing toxicity
(11). AmBisome (manufactured by Nexstar, Inc., San
Dimas, Calif. and provided by Fujisawa USA, Inc., Chicago, Ill.) is a
small unilamellar formulation of amphotericin B which differs from
several other lipid formulations of amphotericin B in that it forms
true liposomes with uniform, stable, spherical single-membrane
vesicles of <0.1 µm in diameter. AmBisome remains
unchanged in the circulation and distributes as intact liposomes to
tissues (1).
Preclinical studies have demonstrated that AmBisome is
as effective or more effective, but less nephrotoxic, than
conventional amphotericin in the treatment of experimental
disseminated candidiasis and invasive pulmonary aspergillosis in
immunocompromised rodents and rabbits (7, 9, 26, 27).
Consistent with these findings are the results of open-label clinical
trials which also demonstrated antifungal efficacy in neutropenic
patients (17-19, 24). No single study, however, has
prospectively studied the safety, tolerance, and
pharmacokinetics of AmBisome at multiple dosages in
neutropenic patients. We therefore studied the safety,
tolerance, and pharmacokinetics of AmBisome in a
sequential-dose-escalation, multidose pharmacokinetic study
administered as empirical antifungal therapy in persistently febrile
neutropenic patients. This study establishes the foundation for
randomized trials designed to investigate the efficacy of AmBisome in persistently febrile neutropenic hosts.
Study design.
The objective of the study was to evaluate the
safety, tolerance, and plasma pharmacokinetics of intravenous
AmBisome at four dosage levels in a population of adult
cancer and bone marrow transplant patients requiring empirical
antifungal therapy. Doses of AmBisome were calculated and
expressed as the amount of amphotericin B administered. For example, a
dose of 50 mg of AmBisome is the administration of an amount
of AmBisome that contains 50 mg of amphotericin B. Patients
were eligible for the study if (i) they were between the ages of 13 and
80 years, undergoing bone marrow transplantation or receiving active
chemotherapy for neoplastic disease, and (ii) they had persistent or
recurrent fever (oral temperature,
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Safety, Tolerance, and Pharmacokinetics of a Small
Unilamellar Liposomal Formulation of Amphotericin B (AmBisome) in
Neutropenic Patients
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
38.0°C) and neutropenia
(absolute neutrophil count, <500/µl) for 5 or more days on
broad-spectrum antibiotics and would normally be given empirical
deoxycholate amphotericin B. No forms of amphotericin B other than the
study drug were allowed during the clinical trial. If patients required
conventional amphotericin B, the study drug was discontinued and
standard therapy was administered. Informed consent was obtained from
the patient or the patient's legally authorized representative prior
to entry. Patients declining enrollment in the study received
conventional amphotericin B.
Pharmacokinetic sampling.
Two-milliliter venous blood
samples were centrifuged, and the plasma fraction was stored at
70°C until analysis. First-dose pharmacokinetic sample collection
times were as follows: prior to the dose, at 1 h (end of
infusion), and at 1.08, 1.5, 2.0, 3, 4, 6, 8, 12, 18, and 24 h
postinfusion. Daily trough samples (immediately prior to the next dose)
were subsequently obtained during daily administration. Last-dose
pharmacokinetic sample time points were then obtained prior to the
dose, at 1 h (end of infusion), and at 1.08, 1.5, 2.0, 3, 4, 6, 8, 12, 18, and 24 h postinfusion, followed by washout samples 3, 7, and 14 days after the last dose of AmBisome.
Analytical methods. Concentrations of amphotericin B in plasma were determined by a high-performance liquid chromatographic assay developed and validated for patients in this study (2). Following methanol deproteinization, amphotericin B and the internal standard, 3-nitrophenol, were separated by reversed-phase chromatography and detected by UV absorbance at 406 nm. Two overlapping standard curves were used: 0.05 to 20 µg/ml and 0.5 to 200 µg/ml. The unweighted correlation coefficient was 0.998 for both curves, with interday and intraday coefficients of variation of 1.8 to 11.2% and 6.9 to 10.1%, respectively.
Pharmacokinetic calculations.
The pharmacokinetic profile of
amphotericin B following AmBisome administration was
determined by noncompartmental analysis. The terminal elimination
half-life (t1/2) was obtained from plasma data
in the postdistribution phase. The elimination rate constant 
was
defined as 0.693/t1/2. The area under the plasma
concentration-time curve and the area under the moment curve from 0 to
24 h (AUC0-24 and AUMC0-24,
respectively) were calculated by the linear trapezoidal method. The
AUC0-
was calculated as AUC0-24 + AUC24-, with AUC24- extrapolated from Ct/, where Ct was the
last measured concentration. The AUMC0- was
calculated similarly, with AUMC24- extrapolated from (Ct × t)/ + (Ct/2). Total body clearance (CL)
was calculated as dose/AUC0-. The volume of
distribution (V) was calculated as CL/. The volume of
distribution at steady state (Vss) was
calculated as [(dose × AUMC0-)/(AUC0-)2] [(dose × infusion time)/(2 × AUC0-)].
Monitoring of safety and tolerance. The following laboratory examinations were performed every other day and on the last day of dosing: hemoglobin, hematocrit, total-leukocyte count with differential, platelet count, prothrombin time, partial thromboplastin time, blood urea nitrogen, and serum creatinine, calcium, potassium, sodium, AST, ALT, lactate dehydrogenase, alkaline phosphatase, total bilirubin, magnesium, and lipase. A specimen for complete urinalysis and blood samples from two separate sites for culture were obtained daily if the patient remained febrile.
Tolerance of infusion-related toxicity was monitored prospectively for each infusion of the study drug. Patients were not premedicated with acetaminophen, diphenhydramine, nonsteroidal anti-inflammatory agents, glucocorticosteroids, or analgesics for the administration of the first dose of AmBisome, thus permitting evaluation of infusion-related toxicity. If infusion-related symptoms developed during that first infusion, one or more of these agents could be administered. A bedside data extraction sheet was utilized by the nursing staff to record serial vital signs during and after infusion, as well as signs and symptoms of infusion-related toxicity. This data extraction sheet then became a source document for reporting infusion-related toxicity. Pulse and blood pressure were monitored immediately before the 1-h infusion, at 15 and 30 min, and at the end of infusion. Between doses, temperature and vital signs were obtained every 4 h during waking hours. Signs, symptoms, and reported side effects associated with study drug infusion or occurring at any time during the study period were recorded and assessed for relationship to the study drug. The relationship of the study drug to possible clinical infusion-related toxicity was assessed by each patient's primary physician. All safety and tolerance data were carefully assessed by an investigator and a clinical monitor in order to ensure that safety criteria had been fulfilled before escalation to the next dosage cohort. Six of eight patients were required to complete therapy with no significant drug-related toxicity before escalation to the next-higher dosage level was permitted.Monitoring of efficacy. Serial blood cultures, urine cultures, and chest radiographs were performed for all febrile neutropenic patients. Blood was cultured by lysis centrifugation (Wampole Laboratories, Cranbury, N.J.) and the BacTAlert system (Organon Teknika Corporation, Durham, N.C.). Computerized tomographic scans and bronchoalveolar lavage were performed as appropriate in evaluating patients for possible invasive fungal infection.
Statistical analysis.
Data are expressed as means ± standard deviations (SD). Comparisons of the mean pharmacokinetic
values between the first and last doses and between different dosage
levels of AmBisome were performed by using a two-tailed,
unpaired Student's t test. Differences in means of clinical
laboratory values and indicators of tolerance to the study drug were
analyzed by the Wilcoxon rank sum test. A P value of 
0.05
was considered to indicate a significant difference.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Study patient population. A total of 36 patients were enrolled in the study and received at least three doses of AmBisome (Table 1). These patients (14 males and 22 females) had a mean age of 38.9 years. Underlying conditions included autologous bone marrow transplantation (n = 16), allogeneic bone marrow transplantation (n = 8), lymphoma (n = 8), acute leukemia (n = 3), and sarcoma (n = 1). The mean duration of administration of the study drug was 9.2 ± 0.8 days.
|
Safety.
Serum creatinine, potassium, and magnesium levels were
not significantly changed in any of the dosage cohorts (Table
2; Fig. 1).
There also was no overall net increase in elevation of serum transaminase levels. There was, however, a trend of increased serum
alkaline phosphatase and bilirubin levels in the overall population, as
well as in individual dosage groups (Table
3). Serum alkaline phosphatase levels
increased by approximately one-half above baseline (P 0.001), and serum bilirubin levels increased two- to fourfold above
baseline (P 0.05). These changes in serum alkaline
phosphatase and bilirubin levels were observed in all dosage groups and
were not dose dependent. Serum lipase did not change from baseline
in any of the dosage cohorts. One patient receiving concomitant
L-asparaginase sustained increases in serum lipase
and amylase levels in association with symptoms of pancreatitis while
receiving AmBisome. However, as he continued to receive AmBisome, serum lipase and amylase levels returned to
baseline. His symptoms resolved, while he continued on the study drug,
in a pattern consistent with L-asparaginase-induced
pancreatitis.
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Tolerance.
AmBisome was associated with minimal
infusion-related toxicity (Table 4). All
infusions of AmBisome were directly monitored; vital signs
and symptoms were recorded in a data collection sheet at the patient's
bedside. Of the 331 infusions that were administered, 15 (5%) were
associated with a temperature elevation of 1°C. Chills were present
during 7 (2%) and rigors during 6 (2%) of the infusions. Hypotension
(in one infusion [0.3%]) and hypertension (in three infusions
[0.9%]) were infrequent, as measured by a >20% decrease or >20%
increase in systolic blood pressure, respectively.
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Pharmacokinetics.
The plasma concentration-time curves of each
dosage cohort on the 1st and last days are depicted in Fig.
2 and 3,
respectively. The means ± SD of the AUC0- values
determined on the 1st day of infusion for the four dosage cohorts (1.0, 2.5, 5.0, and 7.5 mg/kg/day) were 32 ± 15, 71 ± 36, 294 ± 102, and 534 ± 429 µg · h/ml, respectively,
reflecting a nonlinear dosage relationship (Table
5). The increase in AUC exceeding dose
proportionality is consistent with reticuloendothelial saturation and
the subsequent entry of AmBisome into the plasma compartment.
Furthermore, the effect of reticuloendothelial saturation is evidenced
by the increase in AUC0-/dose vis-à-vis the
dose as the dosage increases (Fig. 4). As
the AUC0- increased with escalating dosage, CL
tended to decrease with escalating dosage: from the highest to the
lowest dosage, CL values were 39 ± 22, 51 ± 44, 21 ± 14, and 25 ± 22 µg · h/ml (Table 5). Trough
concentrations were relatively constant for a given patient
and dosage, suggesting negligible plasma accumulation (data not
shown). Of note, the mean ± SD for the AUC0- of
the last dose at 7.5 mg/kg did not increase beyond the last-dose
AUC0- for the 5.0-mg/kg cohort, suggesting a change in
the disposition process through elimination and/or metabolism.
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DISCUSSION |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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This study demonstrated that AmBisome was safe and well tolerated when administered as empirical antifungal therapy to persistently febrile neutropenic patients receiving cytotoxic chemotherapy. The frequency of infusion-related side effects was less than or equal to 5% of all infusions. Only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline, and there were no net increases in hepatic transaminase levels. There were, however, increases in serum bilirubin and alkaline phosphatase levels in patients from all dosage groups. AmBisome followed a nonlinear dosage relationship which was consistent with reticuloendothelial uptake and redistribution. While the study was not designed to assess antifungal therapy, no breakthrough fungal infections developed during the course of empirical antifungal treatment with AmBisome.
In comparison to the well-known infusion-related toxicity of
conventional amphotericin B, AmBisome was associated
with a paucity of infusion-related side effects. Infusion of
amphotericin B is associated with fevers, chills, and rigors in
approximately 70% of patients, necessitating the use of
premedications (8). By comparison, two patients (5%)
receiving AmBisome required premedication in this setting,
which was administered for treatment of urticarial and flushing
reactions. With the exception of the first infusion, all
decisions about premedication were made by the patients'
primary-care physicians. Only 2 to 5% of 331 infusions were associated
with temperature elevation of 1°C, chills, or rigors.
Moreover, fewer than 1% of infusions were associated with hypotension
or hypertension. There was no nausea, vomiting, or headache
associated with AmBisome infusions.
The infusion-related toxicity of conventional amphotericin B is related
to the release of tumor necrosis factor (TNF-
), interleukin 6, and
other cytokines from monocytes and macrophages (3, 15). These studies indicate that encapsulation of amphotericin B by the
liposomal structure of AmBisome may attenuate the release of
these proinflammatory cytokines. Due to their small size and net
negative charge, AmBisome particles are taken up slowly by macrophages of the reticuloendothelial system (RES) (1).
This delayed uptake may result in attenuated release of TNF- from tissue macrophages.
Symptoms not commonly associated with conventional amphotericin B developed during AmBisome infusion in four patients receiving 5.0 and 7.5 mg/kg: facial urticaria, generalized flushing and nausea, dyspnea, and sharp flank pain. These symptoms were treated by stopping the infusion and administering diphenhydramine, followed by resumption of the infusion. In subsequent infusions, two patients were premedicated with diphenhydramine and the remaining two patients received no premedication. Severe infusion-related dyspnea was reported previously for a patient receiving a multilamellar liposomal formulation of amphotericin B (14) and for two patients receiving AmBisome (4). The pathogenesis of the infusion-related reactions due to these two lipid formulations appears to differ. Infusion-related dyspnea due to the multilamellar formulation was associated with hypoxia, pulmonary hypertension, and systemic hypotension (14). By comparison, patients receiving AmBisome had no systemic hypotension, electrocardiographic changes, or hypoxia as measured by pulse oximetry.
There was no significant difference between baseline and end-of-therapy serum creatinine levels in patients receiving AmBisome. Nor was there any significant hypokalemia or hypomagnesemia. These combined findings suggest that AmBisome's reduced nephrotoxicity is related to attenuation of both glomerular and tubular injury. By comparison, conventional amphotericin B compromises both glomerular and tubular function.
Several mechanisms may account for the reduced nephrotoxicity of lipid formulations of amphotericin B. The first mechanism relates to the observations by Mehta et al. (16), who described the liposome-mediated selective transfer of amphotericin B to fungal-cell membranes and away from mammalian-cell membranes, with preferential cytotoxicity for Candida albicans and reduced cytotoxicity for human erythrocytes. This contrasts with conventional amphotericin B, which had cytotoxic effects on both C. albicans and human erythrocytes. Another mechanism is the reduced concentrations of amphotericin B in the kidney relative to the high concentrations achieved in the RES (13, 23, 27). This mechanism alone, however, is not sufficient to explain reduced nephrotoxicity, as AmBisome may accumulate over time in the kidney. A third mechanism, proposed by Perkins et al. (21), is the selective degradation, by fungus-derived phospholipases and lipases, of the liposome, which then releases amphotericin B directly onto the fungal cells. Such lipases and phospholipases are not normally secreted by glomerular cells or renal tubular epithelial cells. A fourth possible mechanism, proposed by Wasan and colleagues, is the preferential binding of the liposome to high-density lipoproteins (HDL), in comparison to conventional amphotericin B, which is bound to low-density lipoproteins (LDL) (30). Renal endothelial cells tend to express high concentrations of LDL, while the hepatic endothelial cells express high concentrations of HDL.
A greater-than-twofold increase in serum creatinine levels was observed in only 3 (8%) of the 36 patients treated in this study. Patients in this study often were receiving concomitant nephrotoxic agents, which included gentamicin, vancomycin, foscarnet, and cyclosporine, which also may have contributed to the elevation of serum creatinine levels. A recently completed randomized, double-blind, multicenter trial of AmBisome versus conventional amphotericin B further demonstrated that the liposomal formulation was significantly less nephrotoxic than conventional therapy and that this safety profile was maintained even with concomitant nephrotoxic agents (28).
Serum transaminase levels were not significantly elevated compared to baseline in any of the dosage cohorts, suggesting that AmBisome may have little if any direct toxic effect on hepatocytes. However, there was elevation of serum alkaline phosphatase and total-bilirubin levels across the dosage cohorts, suggesting an effect on biliary epithelium. Some of these changes may have been related to the effects of chemotherapy, preparative regimens for bone marrow transplantation, graft-versus-host disease, early veno-occlusive disease, and intercurrent septic events rather than to AmBisome. Alternatively, perhaps these concomitant conditions lower the threshold for AmBisome's possible induction of hyperbilirubinemia and elevated alkaline phosphatase levels.
There have been few reports of the plasma pharmacokinetics of AmBisome in humans. Heinemann et al. (10) studied the pharmacokinetics of AmBisome at 3 mg/kg/day versus conventional amphotericin B at 1 mg/kg/day and amphotericin B mixed in a 20% lipid emulsion. Ten bone marrow transplant recipients received AmBisome, which resulted in maximum concentrations of the drug in serum (Cmax) and AUC values 8- and 12-fold greater, respectively, than those reached with conventional amphotericin B at 1 mg/kg/day. The higher Cmax values achieved with AmBisome were related to a Vss fourfold smaller than that obtained with conventional amphotericin B at 1 mg/kg/day.
The plasma pharmacokinetic profile of AmBisome in our
study revealed a nonlinear dose-related pattern, consistent with
reticuloendothelial uptake and redistribution. Plasma
concentrations and AUC0- values increased
disproportionately to the infused dose for the overall dosage range,
both at the initial dosage and in steady state. The CL values of
AmBisome measured on day 1 declined as the dosage of
AmBisome increased, which is consistent with its nonlinear
pharmacokinetic profile. The decreased CL measured from day 1 through
the last day is consistent with the nonlinear saturation-like kinetic
profile of AmBisome. Continued administration of
AmBisome may saturate the reticuloendothelial uptake
mechanisms, resulting in more-sustained plasma levels and decreased CL.
The CL values of AmBisome also declined from the 1st day to
the last day by more than 50% at 1.0, 2.5, and 5.0 mg/kg/day. These
data further suggest that at least one saturable pathway is involved in
the elimination of AmBisome. Reflecting possible
reticuloendothelial deposition with a slow release of drug into the
circulation, plasma samples collected following the last day of dosing
in the 5.0- and 7.5-mg/kg/day dosage groups demonstrated a prolonged
measurable elimination of AmBisome as long as 4 weeks
postdosing.
The plasma pharmacokinetics for the highest-dosage cohort studied, 7.5 mg/kg/day, demonstrated AUC values on day 1 which were consistently greater than the AUC values on the last day. By comparison, the AUC values on the last day for dosages of 1.0, 2.5, and 5.0 mg/kg/day were consistently greater than those on day 1. Such findings have not been described previously for AmBisome or any other lipid formulation of amphotericin B. These results suggest that an alternate mechanism of elimination may have been triggered at the highest dosage of AmBisome. Amphotericin B is eliminated from the circulation by the RES, biliary tract, and urinary tract (12, 27); in addition, elimination of AmBisome from the circulation also is dependent on the RES (1, 11, 13, 23, 26, 27). Higher concentrations of AmBisome may induce a concentration-driven elimination mechanism for amphotericin B, as observed for the renal elimination of carprofen (5) and reticuloendothelial elimination of hemoglobin (6).
As this study was designed to determine safety, tolerance, and pharmacokinetics, conclusions about efficacy in a noncomparative study must be approached with caution. Nevertheless, there were no breakthrough fungal infections in our patients, 24 of whom were autologous or allogeneic bone marrow transplant recipients and hence at risk for invasive fungal infections. Randomized trials will further elucidate the efficacy of AmBisome in the treatment of invasive fungal infections.
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FOOTNOTES |
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* Corresponding author. Mailing address: NCI/POB/IHS, Bldg. 10, Rm. 13N-240, Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: walsht{at}pbmac.nci.nih.gov.
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REFERENCES |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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