1 Clinical Pharmacokinetics Unit, Medical Intensive Care Research Laboratory, Department of Internal Medicine, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck; 2 Intensive Care Unit, Department of Internal Medicine, University of Innsbruck; 3 Infectious Disease Unit, Division of General Internal Medicine, Department of Internal Medicine, University of Innsbruck, Austria
Received 17 August 2002; returned 4 November 2002; revised 9 December 2002; accepted 6 January 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods: Eleven patients required continuous veno-venous haemofiltration (CVVH). Five of them were treated with liposomal AMB (AmBisome) and seven with AMB colloidal dispersion (Amphocil). Six of the critically ill were not undergoing CVVH (three of them treated with liposomal AMB and three with AMB colloidal dispersion).
Results: Significant amounts of AMB are liberated from liposomes or colloidal dispersion during circulation in plasma, where pharmacokinetics mimic that of AMB deoxycholate. Elimination of the remaining lipid-formulated fraction is different and differentially affected by CVVH. Plasma levels of lipid-formulated AMB were significantly higher in patients treated with liposomal AMB than in those treated with AMB colloidal dispersion; clearance of liposomal AMB is enhanced by haemofiltration, whereas elimination of AMB colloidal dispersion is not significantly affected.
Conclusions: The pharmacokinetics of AMB that has been liberated from its lipid moiety is similar under treatment with either liposomal AMB or AMB colloidal dispersion. Since no significant influence of haemofiltration on the pharmacokinetics of liberated AMB has been found, a standard dose of lipid-formulated AMB can be recommended for patients on haemofiltration.
Keywords: pharmacokinetics, amphotericin B deoxycholate, liposomal amphotericin B, amphotericin B colloidal dispersion
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Liposomal AMB comprises spherical liposomes, 4580 nm in diameter. The liposomal bilayer membrane contains hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol and AMB in a molecular ratio of 2:1:0.8: 0.4.7 AMB colloidal dispersion is a lipid formulation containing AMB as a cholesteryl sulphate complex in a molecular ratio of 1:1, forming disc-like structures 74170 nm in diameter and
4 nm thick.8 Free AMB plasma concentrations are claimed to be very low since free AMB is almost insoluble in water. AMB is bound to plasma proteins, mainly to low-density lipoprotein (LDL), after dissociation from its lipid moiety.9 Accumulation of lipid-formulated drug at the sites of fungal infection is said to be responsible for its efficacy, in spite of the absence of free AMB in plasma.8,1012
Several studies on the pharmacokinetics of AMB deoxycholate, liposomal AMB and AMB colloidal dispersion have been performed.1318 Data in patients on haemofiltration, however, are very sparse and only total AMB has been measured so far.1820 Separation of liberated AMB from lipid-formulated AMB for differential pharmacokinetics has not been performed.
Since acute renal failure and the need for haemofiltration occur frequently in critically ill patients with multiorgan failure, the influence of continuous veno-venous haemofiltration (CVVH) on the pharmacokinetics of lipid-formulated AMB would have great relevance for appropriate dosage. In this study, the pharmacokinetics of lipoprotein-bound and lipid-formulated AMB were separately determined in critically ill patients. Elimination of lipid-formulated and lipoprotein-bound AMB by haemofiltration was studied.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The study was performed between October 1999 and March 2001. A total of 16 consecutive critically ill patients requiring AMB treatment for proposed or proven invasive fungal infection were included.21 Informed consent was obtained when possible, or patients were informed about the scientific use of their clinical data after waking from analgesia/sedation. The study was performed according to the guidelines of the local ethics committee and to Austrian law. The main characteristics of the patients, their treatments and the number of assays performed in each patient are listed in Table 1.
|
Four patients received AMB deoxycholate (patients 14). Two of them were undergoing haemofiltration for irreversible, terminal renal failure (patients 1 and 2). Seven patients were treated with liposomal AMB (patients 1 and 510), five of whom were receiving CVVH (patients 1 and 58), whereas three were not (patients 5, 9 and 10). Eight patients were undergoing therapy with AMB colloidal dispersion (patients 2, 7 and 1116), seven required CVVH (patients 2, 7 and 1115), three did not (patients 1416; see Table 1). Thus six patients were allocated to more than one group: patients 1 and 2 were changed from liposomal AMB to AMB deoxycholate therapy. Patient 7 had to be moved from AMB colloidal dispersion to liposomal AMB because of acute toxicity. Patients 5, 14 and 15 were weaned from haemofiltration because their renal function had recovered (see Table 1).
Drug administration and preparation
AMB deoxycholate (Bristol-Myers-Squibb, Vienna, Austria), liposomal AMB (AmBisome NeXstar Pharmaceuticals, Boulder, CO, USA) and AMB colloidal dispersion (Amphocil, Sequus Pharmaceuticals Inc., Menlo Park, CA, USA) were dissolved, as recommended by the manufacturer, and diluted in 500 mL of 5% dextrose. The infusion time was 4 h for AMB deoxycholate, liposomal AMB and AMB colloidal dispersion. The dosages are shown in Table 3. All assays were performed under steady-state conditions (after a mean AMB treatment duration of 7.78 days).
|
Vascular access was obtained by insertion of a double-lumen dialysis catheter (Quinton Marhurkar, Quinton Instrument Company, Bothall, WA, USA) into a central vein. CVVH was pump-driven (Dialyse Technik, Ettlingen, Germany) using an Equaline system (Medica, Medolla, Italy) and a hollow 0.71 m2 polysulphone capillary fibre haemofilter (Baxter PSHF 700, Minntech Corporation, Minneapolis, MN, USA). Replacement solution (HF-Bic 35-210 Fresenius, Bad Homburg, Germany) consisting of 140 mmol/L sodium, 2 mmol/L potassium, 15 mmol/L calcium, 0.5 mmol/L magnesium, 110 mmol/L chloride, 35 mmol/L bicarbonate and 1 g/L glucose was infused at an adequate rate to maintain patient fluid balance. The replacement fluid was administered in the pre-dilution mode. Interruption of the haemofiltration process occurred during some of the sampling periods due to clotting of the filter or diagnostic procedures, such as computer-assisted tomography. Details of the haemofiltration protocols are described in Table 2.
|
Arterial blood samples of 2 mL were drawn into heparinized vials (Monovette, Sarstedt, Nümbrecht, Germany) before, as well as 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 h after the start of the respective infusion. In one experiment (patient 2, experiment 2), venous blood samples were also drawn, to provide a comparison between arterial and venous plasma concentrations of AMB. Samples were centrifuged immediately (10 min, 2000 rpm), and plasma was frozen and stored at 75°C. Plasma levels of lipoprotein-bound and lipid-formulated AMB were separated using Bond Elut C18 (100 mg) solid-phase extraction cartridges (Varian, Palo Alto, CA, USA). The lipid-formulated substance was not retained on the cartridge, whereas plasma-lipoprotein-bound AMB as well as AMB deoxycholate was retained and eluted off the column with 60% acetonitrile in water, as described previously.22 HPLC analysis was performed with a Lichrosorb RP-8 column (200 x 4.6 mm; 5 µm; Agilent Technologies, Palo Alto, CA, USA) connected to a Zorbax SB-C8 precolumn (12.5 x 4.6 mm; 5 µm; Agilent Technologies). AMB was measured by a UV detector at 405 nm. The detection limit was 0.005 µg/mL.22 Total AMB plasma concentrations were obtained by the addition of concentrations of lipoprotein-bound and lipid-formulated AMB. Pharmacokinetic parameters for total AMB were derived from these calculated data.
Pharmacokinetic calculations and statistical evaluation
Pharmacokinetics were calculated using a non-compartmental model. The calculations were performed with the Kinetica 2000 program (InnaPhase Corporation, Champs-sur-Marne, France). The area under the concentrationtime curve from time zero to time n of the last sample (AUC0n) was computed using the log linear method, whenever the concentration in a trapezoid decreased, or the trapezoidal method was applied when the concentration increased (Cn > Cn1). AUC0n is defined as AUC0n from t = 0 to tlast = 24 h, AUC0n is AUC024.
The statistical significance of the results was evaluated by the MannWhitney U-test.
AMB concentrations in ultrafiltrate and urine
Ultrafiltrate samples were drawn from the ultrafiltrate outlet of the haemofilter. Concentrations of free and lipid-formulated AMB were determined as described.22 Calculation of haemofilter clearance was performed using the formula:
CLHF = mean UFR x AUC024 UF/AUC024 PL
where AUC024 UF is the AUC024 in the ultrafiltrate and AUC024 PL is the AUC024 in the plasma.
The sieving coefficient (SC) is the AUC024 measured in ultrafiltrate divided by the plasma AUC024:
SC = AUC024 UF/AUC 024 PL
Urine samples were drawn from a urinary catheter. Renal clearance of liberated, lipid-formulated and total AMB was determined in one patient treated with liposomal AMB, who was receiving CVVH (patient 5), but had residual diuresis of 1200 mL per day, and in two patients treated with AMB colloidal dispersion (patient 15 during CVVH and patient 14 after recovery of renal function and weaning from haemofiltration). In patient 5, 11 urine samples and 11 plasma samples were drawn on two different days, in patient 15, eight urine and eight plasma samples on two days. In patient 14, 12 urine and 12 plasma samples were analysed. Renal clearance was calculated using the formula:
CLUrine = Urine flow rate x CUrine/CPL
Extraction of AMB from haemofilters
AMB adsorption to haemofilters was analysed in three patients (patient 3, who had received liposomal AMB 300 mg, patient 5, liposomal AMB 200 mg and patient 10, AMB colloidal dispersion 100 mg). After the monitoring period, the plastic casings of the used haemofilters were opened and the polysulphone hollow fibres cut into small pieces 1 mm long, and suspended in water. Total AMB was extracted with acetonitrile (Merck) by shaking and incubation at 37°C overnight. Acetonitrile was removed with an evaporator at 60°C, and the pellets were resuspended in water. After purification by Bond ElutC18 cartridges, total AMB was measured by HPLC as described.22
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The timeconcentration profiles of lipoprotein-bound and lipid-formulated AMB for patients treated with AMB deoxycholate, liposomal AMB and AMB colloidal dispersion on and off haemofiltration are displayed in Figure 1. Table 3 shows the main pharmacokinetic parameters for lipoprotein-bound AMB for patients on therapy with AMB deoxycholate, as well as for lipoprotein-bound, lipid-formulated and total AMB during treatment with liposomal AMB and AMB colloidal dispersion. Cmax and AUC024 of total and lipid-formulated AMB were significantly higher in patients on haemofiltration treated with liposomal AMB than in patients treated with AMB colloidal dispersion (P = 0.0045 for Cmax and for AUC024 for lipid-formulated and for total AMB). During CVVH, clearance (CL) and Vd of total and lipid-formulated AMB were significantly lower in patients on liposomal AMB than in those on AMB colloidal dispersion (lipid-formulated AMB: P = 0.0045 for CL, P = 0.0074 for Vd, total AMB: P = 0.0185 for CL, P = 0.0118 for Vd). A significant difference between the haemofiltration group and the control group was only observed for the clearance of lipid-formulated and total AMB during therapy with liposomal AMB; it was higher in the haemofiltration group (0.198 L/h/kg versus 0.079 L/h/kg, P = 0.0253 and 0.140 L/h/kg versus 0.061 L/h/kg, P = 0.0369, respectively, see Table 3).
|
The half-life of protein-bound AMB during AMB deoxycholate treatment was shorter when CVVH was performed. In patients treated with liposomal AMB, however, it appeared to be longer in the haemofiltration group; for AMB colloidal dispersion treatment, no difference in t1/2 of protein-bound AMB was found between the haemofiltration and control groups. The half-life of liposomal AMB was unchanged by CVVH, whereas that of AMB colloidal dispersion was enhanced in the CVVH group (see Table 3).
The clearance and volume of distribution of protein-bound as well as of lipid-formulated AMB were enhanced in the haemofiltration group, but the difference was significant only for liposomal AMB (lipid-formulated fraction), as mentioned above. For clearance of AMB colloidal dispersion (lipid-formulated fraction), no influence of haemofiltration was found (see Table 3).
No correlation between variables of the haemofiltration process, interruptions, running time (age) of the haemofilter, ultrafiltration rate or blood flow was found by linear regression.
In one patient, who was treated with AMB deoxycholate, arterial and venous AMB plasma concentrations were determined. The venous AMB concentration was slightly higher (by 6.9% on average). The difference was most pronounced during the infusion of the drug.
AMB concentrations in ultrafiltrate, sieving coefficient and haemofilter clearance
AMB concentrations in the ultrafiltrate of patient 1 were measured during treatment with AMB deoxycholate. The maximum AMB level in ultrafiltrate was observed at the end of infusion and accounted for 0.23 µg/mL; Cmax in plasma was 0.76 µg/mL. The sieving coefficient for AMB was 0.29, the haemofilter clearance (CLHF) 0.42 L/h (8.10% of total CL).
Liberated AMB and liposomal AMB were measured in the ultrafiltrates of three patients on therapy with liposomal AMB. The peak concentration of free AMB appeared in ultrafiltrate 34 h after the start of the infusion of liposomal AMB, and accounted for 0.079 µg/mL 0.039 (mean + S.D.). The mean plasma peak concentration in the same three patients was 1.52 µg/mL. Small amounts of free AMB could be detected in all ultrafiltrate samples. The mean sieving coefficient for free AMB was 0.16 during therapy with liposomal AMB. Liposomal AMB was not detected in the majority of ultrafiltrate samples; only at the end of infusion (34 h after the start) could small amounts (mean CmaxUF 0.065 µg/mL) be found. The sieving coefficient for liposomal AMB was below 0.04, and the clearance of liposomal AMB by haemofiltration was as low as 0.06 L/h (0.40% of the total body clearance of liposomal AMB).
In the ultrafiltrate of patients treated with AMB colloidal dispersion, the mean peak concentration of free AMB was 0.095 µg/mL (+0.012). The average clearance of free AMB by haemofiltration was 0.25 L/h during therapy with AMB colloidal dispersion (2.20% of total clearance). Only in a few ultrafiltrate samples was AMB colloidal dispersion (lipid-formulated form) detected (0.201 µg/mL, 1.5 h after start of infusion). The sieving coefficient of AMB colloidal dispersion was 0.07 and the haemofilter clearance 0.20 L/h (0.03% of the total clearance of AMB colloidal dispersion). The sieving coefficient of total AMB (AMB colloidal dispersion and free AMB) was 0.29, the haemofilter clearance 0.142 L/h (2.30% of total body clearance).
AMB recovered from haemofilter
Adsorption of AMB to haemofilters was analysed in three used haemofilters. Two had been run in patients treated with liposomal AMB, one was taken from a patient who had received AMB colloidal dispersion. AMB was recovered from all haemofilters. A total of 0.53 µg and 0.39 µg of AMB was recovered from the haemofilters of patients treated with liposomal AMB, and 0.16 µg from the haemofilter run in the patient treated with AMB colloidal dispersion.
Renal AMB clearance
Renal clearance of liposomal AMB was measured in a patient who was undergoing haemofiltration, but had a residual diuresis of 1200 mL per day (patient 5). In this patient, the mean renal clearance of free AMB was 0.133 L/h (0.97% of total clearance), renal clearance of lipid-formulated 0.014 L/h (0.15% of total body clearance) and that of total AMB was 0.052 L/h (0.86% of total body clearance). In patient 15, who was on haemofiltration, after administration of AMB colloidal dispersion, mean renal clearance of free AMB accounted for 0.294 L/h (1.10% of total clearance of free AMB), clearance of lipid-formulated 0.173 L/h (0.96% of total clearance) and that of total AMB 0.363 L/h (1.70% of total clearance). In patient 14, who had obtained AMB colloidal dispersion and had approximately normal renal function, renal clearance of free AMB was as low as 0.004 L/h (0.04% of total clearance), whereas no renal clearance of lipid-formulated AMB could be identified (urine levels were below the detection limit).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Plasma pharmacokinetics of AMB deoxycholate have been studied by other investigators.13,24 Because of its nephrotoxicity, this substance is not usually administered to patients with renal failure treated with haemofiltration. In terminal renal failure, however, when recovery of renal function cannot be expected, therapy with AMB deoxycholate is possible. AMB plasma levels during treatment with AMB deoxycholate were measured in two critically ill patients with normal renal function and in two patients with terminal renal failure, who were on CVVH. A high variability of AMB pharmacokinetics is known.13 Pharmacokinetic data derived from our two patients not undergoing haemofiltration are in agreement with the literature.8,18 No pharmacokinetic data for patients receiving haemofiltration have been published, to our knowledge. In our two patients undergoing CVVH, we observed a slightly enhanced AMB clearance and a higher volume of distribution, whereas peak concentrations and AUC024 were somewhat lower in comparison with patients not receiving CVVH. A slightly enhanced elimination of AMB may be considered in patients administered haemofiltration.
Up to now, the pharmacokinetics of liposomal AMB have been studied in only one patient undergoing haemofiltration18 and in another, haemodiafiltration.20 Peak and trough levels were measured in one additional patient treated with CVVH.19 No effect of haemofiltration on the pharmacokinetics of total AMB levels was found in these patients. The pharmacokinetics of AMB colloidal dispersion have been investigated only in healthy volunteers.15,16 In the present study, total AMB levels have been calculated by adding lipoprotein-bound and lipid-formulated AMB, for comparison with existing data. While volume of distribution and clearance observed in our critically ill patients are in good agreement with previously published data, the half-life and AUC024 were much lower in critically ill patients (21 versus 235 h and 9.59 versus 56.8 mgh/L).
In patients treated with liposomal AMB, Cmax and AUC024 of total and lipid-formulated AMB were significantly higher than in those who had received AMB colloidal dispersion at comparable doses, whereas CL and Vd were significantly lower. This difference was observed in patients treated with CVVH as well as those not undergoing haemofiltration. In patients not receiving haemofiltration, different elimination rates of total AMB from plasma have been described, and explained as resulting from rapid particle uptake of AMB colloidal dispersion by the reticulo-endothelial system, while the smaller particles of liposomal AMB remain in the circulation for longer.11,12 When the pharmacokinetics of liberated lipoprotein-bound AMB were compared, however, no significant difference between liposomal AMB and AMB colloidal dispersion was noted. There was a tendency for lower plasma levels during haemofiltration in the group treated with AMB colloidal dispersion (Cmax of lipoprotein-bound AMB was 0.4 µg/mL versus 0.6, and AUC024 was 3.61 versus 8.54 mgh/L, not significant), which may also, in part, be related to the fact that doses administered were not identical. The enhanced volume of distribution, however, which was found during haemofiltration, may be the most probable explanation of the increased removal of AMB from plasma.
Beside elimination by ultrafiltration, adsorption to the haemofilter membrane may influence the pharmacokinetics of drugs during CVVH.25,26 This phenomenon is difficult to assess, since it depends on the physicochemical properties of the haemofilter membrane and several other variables of the haemofiltration process, such as ultrafiltration rate and blood flow through the haemofilter. We addressed this problem by dissecting three haemofilters after usage and estimating the amount of AMB recovered. Relatively low amounts of the drug were recovered, and no excessive adsorption to the haemofilter has to be expected.
The clearance of lipoprotein-bound AMB by ultrafiltration contributed to the total clearance to a low extent (2%); for lipid-formulated AMB there was almost no clearance by ultrafiltration. The sieving coefficient and the renal clearance of lipid-formulated AMB were low.
The main advantage of lipid-formulated AMB is the increased therapeutic index achieved by reduced toxicity. Compared with liposomal AMB, AMB colloidal dispersion has a higher acute toxicity.2729 This was also observed in our study (patient 7 had to be moved from AMB colloidal dispersion to liposomal AMB because of infusion-related chills and fever). The difference in toxicity has been thought to be due to the lower plasma levels of free AMB with liposomal AMB, when compared with AMB colloidal dispersion.12 Since we found similar plasma concentrations of liberated lipoprotein-bound AMB in patients treated with the two lipid formulations, our data do not support this hypothesis.
Whereas the pharmacokinetics of AMB liberated from the lipid moiety are similar to those of AMB deoxycholate, the pharmacokinetics of lipid-formulated AMB are different. Furthermore, the pharmacokinetic parameters of liposomal AMB differ from those of AMB colloidal dispersion: clearance and volume of distribution of AMB colloidal dispersion exceed those of liposomal AMB by >10- and 50-fold, respectively. In critically ill patients, the pharmacokinetics of liberated AMB are similar, whether undergoing haemofiltration or not. The significant influence of haemofiltration on AMB elimination was observed only for liposomal AMB, where the clearance was enhanced by a factor of two. Clearance of AMB colloidal dispersion also appeared to be increased during haemofiltration, but this difference was not significant. Thus pharmacokinetics of lipoprotein-bound and lipid-bound AMB are different and differentially influenced by CVVH.
Since the amount of AMB that has dissociated from its lipid moiety during treatment with lipid-formulated AMB has not been investigated in critically ill patients so far, its relevance for fungicidal efficacy of the drug is not clear. A mechanism without dissociation of AMB from the lipid moiety in the circulation has been suggested. Phospholipases are hypothesized to be involved in the liberation of AMB from its lipid moiety at the target site.10,12 In the light of our observations, a model covering the activity of free AMB is attractive. A head-to-head study comparing the clinical efficacy of liposomal AMB and AMB colloidal dispersion is still lacking. Nevertheless, clinical studies on liposomal AMB and on AMB colloidal dispersion have confirmed a comparable clinical efficacy for both preparations.9,3039 This provides additional indirect evidence of the impact of dissociation of AMB from the lipid moiety, since plasma levels are similar only for the liberated, lipoprotein-bound fraction.
In this study of consecutive cases, patient sample discrepancies are likely to reflect variations in the actual patient population of intensive care units. For a more detailed pharmacokinetic study, a standardized protocol with inclusion and exclusion criteria and a standardized haemofiltration procedure would be required.
In conclusion, in critically ill patients with renal failure treated with CVVH, AMB does not accumulate when liposomal AMB or AMB colloidal dispersion is administered at the standard dose. Elimination even seems to be slightly enhanced, especially that of liposomal AMB. Based on the pharmacokinetics of the active moiety of the preparations, free AMB, which is lipoprotein-bound in the plasma, no superiority of either of the two lipid formulations (liposomal AMB or AMB colloidal dispersion) has been shown in the treatment of critically ill patients on CVVH, and administration of the standard dose of 34 mg/kg can be recommended for this group of patients.
![]() |
Footnotes |
---|
Present address. Dipartimento di Ingegneria dei Materiali, Università di Trento, via Mesiano 77, I-38050 Trento, Italy.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . DAmelio, L. F., Wagner, B., Azimuddin, S., Sutyak, J. P. & Hammond, J. S. (1995). Antibiotic patterns associated with fungal colonization in critically ill surgical patients. American Surgeon 6, 104953.
3
.
Walsh, T. J., Finberg, R. W., Arndt, C., Hiemenz, J., Schwartz, C., Bodensteiner, D. et al. (1999). Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. New England Journal of Medicine 340, 76471.
4 . Wingard, J. R., Kubilis, P., Lee, L., Yee, G., White, M., Walshe, L. et al. (1999). Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clinical Infectious Diseases 29, 14027.[CrossRef][ISI][Medline]
5 . Fanos, V. & Cataldi, L. (2000). Amphotericin B-induced nephrotoxicity: a review. Journal of Chemotherapy 12, 46370.[ISI][Medline]
6
.
Eriksson, U., Seifert, B. & Schaffner, A. (2001). Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. British Medical Journal 322, 57982.
7 . Adler-Moore, J. P. & Proffitt, R. T. (1993). Development, characterization, efficacy and mode of action of AmBisome, a unilamellar liposomal formulation of amphotericin B. Journal of Liposome Research 3, 42950.
8
.
Boswell, G. W., Buell, D. & Bekersky, I. (1998). AmBisome (liposomal amphotericin B): a comparative review. Journal of Clinical Pharmacology 38, 58392.
9 . Ridente, Y., Aubard, J. & Bolard, J. (1999). Absence in amphotericin B-spiked plasma of the free monomeric drug, as detected by SERS. FEBS Letters 446, 2826.
10 . Wasan, K. M. & Lopez-Berestein, G. (1996). Characteristics of lipid-based formulations that influence their biological behavior in the plasma of patients. Clinical Infectious Diseases 23, 112638.[ISI][Medline]
11 . Hiemenz, J. W. & Walsh, T. J. (1996). Lipid formulations of amphotericin B: recent progress and future directions. Clinical Infectious Diseases 22, Suppl. 2, S13344.[ISI][Medline]
12 . Wong-Beringer, A., Jacobs, R. A. & Guglielmo, B. J. (1998). Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clinical Infectious Diseases 27, 60318.[ISI][Medline]
13 . Benson, J. M. & Nahata, M. C. (1989). Pharmacokinetics of amphotericin B in children. Antimicrobial Agents and Chemotherapy 33, 198993.[ISI][Medline]
14 . Hoeprich, P. D. (1990). Elimination half-life of amphotericin B. Journal of Infection 20, 1735.[ISI][Medline]
15 . Sanders, S. W., Buchi, K. N., Goddard, M. S., Lang, J. K. & Tolman, K. G. (1991). Single-dose pharmacokinetics and tolerance of a cholesteryl sulfate complex of amphotericin B administered to healthy volunteers. Antimicrobial Agents and Chemotherapy 35, 102934.[ISI][Medline]
16 . Janknegt, R., de Marie, S., Bakker-Woudenberg, I. A. & Crommelin, D. J. (1992). Liposomal and lipid formulations of amphotericin B. Clinical Pharmacokinetics 23, 27991. [ISI][Medline]
17 . Villani, P., Regazzi M. B., Maserati, R., Viale, P., Alberici, F. & Giacchino, R. (1996). Clinical and pharmacokinetic evaluation of a new lipid-based delivery system of amphotericin B in AIDS patients. Arzneimittel-Forschung Drug Research 46, 4459.
18 . Heinemann, V., Bosse, D., Jehn, U., Kähny, B., Wacholz, K., Debus, A. et al. (1997). Pharmacokinetics of liposomal amphotericin B (AmBisome) in critically ill patients. Antimicrobial Agents and Chemotherapy 41, 127580.[Abstract]
19 . Humphreys, H., Oliver, D., Winter, R. & Warnock, D. W. (1994). Liposomal amphotericin B and continuous veno-venous haemofiltration. Journal of Antimicrobial Chemotherapy 33, 10701.
20 . Tomlin, M. & Priestly, G. S. (1995). Elimination of liposomal amphotericin B by hemodiafiltration. Intensive Care Medicine 21, 699700.[ISI][Medline]
21 . Khoo, S. H., Bond, J. & Denning, D. W. (1994). Administering amphotericin Ba practical approach. Journal of Antimicrobial Chemotherapy 33, 20313.[Abstract]
22 . Egger, P., Bellmann, R. & Wiedermann, C. J. (2001). Determination of amphotericin B, liposomal amphotericin B and amphotericin B colloidal dispersion in plasma by high-performance liquid chromatography. Journal of Chromatography B: Biomedical Applications 760, 30713.[CrossRef]
23 . Groll, A. H., Giri, N., Petraitis, V., Petraitiene, R., Candelario, M., Bacher, J. S. et al. (2000). Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. Journal of Infectious Diseases 182, 27482.[CrossRef][ISI][Medline]
24 . Atkinson, A. J., Jr & Bennett, J. E. (1978). Amphotericin B pharmacokinetic in humans. Antimicrobial Agents and Chemotherapy 13, 2716.[ISI][Medline]
25 . Kroh, U. F. (1995). Drug administration in critically ill patients with acute renal failure. New Horizons 3, 74859.[Medline]
26 . Kroh, U. F., Dinges, G. K., Lukasewitz, P., Steinhausser, W. U., Holl, T. J. & Lennartz, H. (1998). Elimination of drugs by the new polyamide haemofilter FH77H during various in vitro conditions. Blood Purification 16, 4956.[CrossRef][ISI][Medline]
27 . Hanson, L. H. & Stevens, D. A. (1992). Comparison of antifungal activity of amphotericin B deoxycholate suspension with that of amphotericin B cholesteryl sulfate colloidal dispersion. Antimicrobial Agents and Chemotherapy 36, 4868.[Abstract]
28 . White, M. H., Anaissie, E. J., Kusne, S., Wingard, J. R., Hiemenz, J. W., Cantor, A. et al. (1997). Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clinical Infectious Diseases 24, 63542.[ISI][Medline]
29 . White, M. H., Bowden, R. A., Sandler, E. S., Graham, M. L., Noskin, G. A., Wingard, J. R. et al. (1998). Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clinical Infectious Diseases 27, 296302.[ISI][Medline]
30 . Zoubek, A., Emminger, W., Emminger-Schmidmeier, W., Peters, C., Pracher, E., Grois, N. et al. (1992). Conventional vs. liposomal amphotericin B in immunosuppressed children. Pediatric Hematology and Oncology 9, 18790.[ISI][Medline]
31 . Ringden, O., Tollemar, J. & Tyden, G. (1992). Liposomal amphotericin B. Lancet 339, 374.[CrossRef]
32 . Allende, M. C., Lee, J. W., Francis, P., Garrett, K., Dollenberg, H., Berenguer, J. et al. (1994). Dose-dependent antifungal activity and nephrotoxicity of amphotericin B colloidal dispersion in experimental pulmonary aspergillosis. Antimicrobial Agents and Chemotherapy 38, 51822.[Abstract]
33 . Mills, W., Chopra, R., Linch, D. C. & Goldstone, A. H. (1994). Liposomal amphotericin B in the treatment of fungal infections in neutropenic patients: a single centre experience of 133 episodes in 116 patients. British Journal of Haematology 86, 75460.[ISI][Medline]
34 . Ringden, O., Tollemar, J., Dahllof, G. & Tyden, G. (1994). High cure rate of invasive fungal infections in immunocompromised children using AmBisome. Transplantation Proceedings 26, 18790.[ISI][Medline]
35 . Ng, T. T. C. & Denning, D. W. (1995). Liposomal amphotericin B (AmBisome) therapy of invasive fungal infections: evaluation of United Kingdom compassionate use data. Archives of Internal Medicine 155, 10938.[Abstract]
36 . Bowden, R. A., Cays, M., Gooley, T., Mamelok, R. D. & van Burik, J. (1996). Phase I study of amphotericin B colloidal dispersion for the treatment of invasive fungal infections after marrow transplant. Journal of Infectious Diseases 173, 120815.[ISI][Medline]
37
.
Anaissie, E. J., Mattiuzzi, G. N., Miller, C. B., Noskin, G. A., Gurwith, M. J., Mamelok, R. D. et al. (1998). Treatment of invasive fungal infections in renally impaired patients with amphotericin B colloidal dispersion. Antimicrobial Agents and Chemotherapy 42, 60611.
38 . Leenders, A. C., Daenen, S., Jansen, R. L., Hop, W. C., Lowenberg, B., Wijermans, P. W. et al. (1998). Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. British Journal of Haematology 103, 20512.[CrossRef][ISI][Medline]
39 . Blau, I. W. & Fauser, A. A. (2000). Review of comparative studies between conventional and liposomal amphotericin B (Ambisome) in neutropenic patients with fever of unknown origin and patients with systemic mycosis. Mycoses 43, 32532.[CrossRef][ISI][Medline]