scholarly journals Compartmentalized Intrapulmonary Pharmacokinetics of Amphotericin B and Its Lipid Formulations

2006 ◽  
Vol 50 (10) ◽  
pp. 3418-3423 ◽  
Author(s):  
Andreas H. Groll ◽  
Caron A. Lyman ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Derek Armstrong ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Lung Tissue ◽  
Colloidal Dispersion ◽  
Pharmacokinetic Parameters ◽  
Dilution Method ◽  
Lipid Complex ◽  
Drug Concentrations ◽  
Amphotericin B Deoxycholate ◽  
Amphotericin B Lipid Complex ◽  
Lipid Formulations

ABSTRACT We investigated the compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations in healthy rabbits. Cohorts of three to seven noninfected, catheterized rabbits received 1 mg of amphotericin B deoxycholate (DAMB) per kg of body weight or 5 mg of either amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex (ABLC), or liposomal amphotericin B (LAMB) per kg once daily for a total of 8 days. Following sparse serial plasma sampling, rabbits were sacrificed 24 h after the last dose, and epithelial lining fluid (ELF), pulmonary alveolar macrophages (PAM), and lung tissue were obtained. Pharmacokinetic parameters in plasma were derived by model-independent techniques, and concentrations in ELF and PAM were calculated based on the urea dilution method and macrophage cell volume, respectively. Mean amphotericin B concentrations ± standard deviations (SD) in lung tissue and PAM were highest in ABLC-treated animals, exceeding concurrent plasma levels by 70- and 375-fold, respectively (in lung tissue, 16.24 ± 1.62 versus 2.71 ± 1.22, 6.29 ± 1.17, and 6.32 ± 0.57 μg/g for DAMB-, ABCD-, and LAMB-treated animals, respectively [P = 0.0029]; in PAM, 89.1 ± 37.0 versus 8.92 ± 2.89, 5.43 ± 1.75, and 7.52 ± 2.50 μg/ml for DAMB-, ABCD-, and LAMB-treated animals, respectively [P = 0.0246]). By comparison, drug concentrations in ELF were much lower than those achieved in lung tissue and PAM. Among the different cohorts, the highest ELF concentrations were found in LAMB-treated animals (2.28 ± 1.43 versus 0.44 ± 0.13, 0.68 ± 0.27, and 0.90 ± 0.28 μg/ml in DAMB-, ABCD-, and ABLC-treated animals, respectively [P = 0.0070]). In conclusion, amphotericin B and its lipid formulations displayed strikingly different patterns of disposition in lungs 24 h after dosing. Whereas the disposition of ABCD was overall not fundamentally different from that of DAMB, ABLC showed prominent accumulation in lung tissue and PAM, while LAMB achieved the highest concentrations in ELF.

scholarly journals Comparative Efficacies, Toxicities, and Tissue Concentrations of Amphotericin B Lipid Formulations in a Murine Pulmonary Aspergillosis Model

2006 ◽  
Vol 50 (6) ◽  
pp. 2122-2131 ◽  
Author(s):  
Jon A. Olson ◽  
Jill P. Adler-Moore ◽  
Julie Schwartz ◽  
Gerard M. Jensen ◽  
Richard T. Proffitt
Keyword(s):  
Amphotericin B ◽  
High Performance ◽  
Therapeutic Index ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Drug Concentrations ◽  
Kidney Morphology ◽  
Amphotericin B Lipid Complex ◽  
Effective Use ◽  
Lipid Formulations

ABSTRACT Invasive aspergillosis, an important cause of morbidity and mortality in immunosuppressed (IS) patients, is often treated with amphotericin B lipid formulations. In the present study, liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) were compared in treatment of murine pulmonary aspergillosis. Uninfected, IS mice were treated for 4 days with 1, 4, 8, or 12 mg L-AMB or ABLC/kg of body weight, and their lungs were analyzed by high-performance liquid chromatography for drug concentrations. IS mice intranasally challenged with Aspergillus fumigatus were treated with 12, 15, or 20 mg/kg L-AMB or ABLC and monitored for survival, fungal burden (CFU), and tissue drug concentration. Blood urea nitrogen (BUN) levels and kidney histopathology were determined for uninfected and infected mice given 15 or 20 mg/kg L-AMB or ABLC. The results showed that both drugs had therapeutic levels of drug (>3.0 μg/g) in the lungs of uninfected or infected mice, and 24 h after the last dose, ABLC levels were significantly higher than L-AMB levels (P < 0.02). L-AMB and ABLC at 12 mg/kg both produced 57% survival, but only L-AMB at 15 or 20 mg/kg further increased survival to 80 to 90%, with BUN levels and kidney morphology similar to those of controls. Survival at 15 or 20 mg/kg ABLC was not significantly different than that of controls, and BUN levels were significantly elevated, with tubular alterations in uninfected animals and acute necrosis in kidney tubules of infected animals. In conclusion, although both drugs were effective in prolonging survival at 12 mg/kg, the reduced nephrotoxicity of L-AMB increased its therapeutic index, allowing for its safe and effective use at 15 or 20 mg/kg.

Analisi Costo-Efficacia di Amfotericina B Liposomiale (L-AmB) versus Amfotericina B Complesso Lipidico (ABLC) nel trattamento empirico della neutropenia febbrile

2005 ◽  
Vol 6 (4) ◽  
pp. 333-347
Author(s):  
Mario Eandi
Keyword(s):  
Febrile Neutropenia ◽  
Amphotericin B ◽  
Broad Spectrum ◽  
Cost Minimization ◽  
Colloidal Dispersion ◽  
Lipid Complex ◽  
Fungicidal Action ◽  
Amphotericin B Deoxycholate ◽  
Lipid Formulations ◽  
Compromised Patients

Current international guidelines for the management of immuno-compromised patients with febrile neutropenia recommend a systemic antimicrobial therapy if fever hasn’t receded after three days of antibiotic treatment. Amphotericin B remains the gold standard because of its broad spectrum fungicidal action and minimal resistance development risk. Nonetheless, therapeutic use of the standard formulation, Amphotericin B deoxycholate, is limited by its toxicity, especially on the kidneys. To counteract this, amphotericin B has been encapsulated in liposomes, a process which reduces its toxicity and allows higher doses to be given. Three lipid formulations have been developed and are now available in most countries: amB colloidal dispersion (ABCD), amB lipid complex (ABLC), and liposomal amB (L-AmB). These lipid formulations differ in pharmacodynamics and pharmacokinetics, and can’t therefore be considered interchangeable. Besides, they are more expensive than Amphotericin B deoxycholate. Aim of the study is to perform a cost/effectiveness analysis (CEA) comparing L-AmB (3mg/kg/die or 5mg/kg/ die) and ABLC (5mg/kg/die) as first-line antimicrobial empirical treatments in immuno-compromised patients with febrile neutropenia resistant to broad spectrum antibiotics. Secondly, we present a cost-minimization analysis (CMA) of the considered alternatives, assuming the same efficacy for all treatments. At the end we value the principal cost items from the point of view of the Italian Health Service, with a particular focus on the economic burden caused by adverse reactions.

scholarly journals Dose Range Evaluation of Liposomal Nystatin and Comparisons with Amphotericin B and Amphotericin B Lipid Complex in Temporarily Neutropenic Mice Infected with an Isolate of Aspergillus fumigatus with Reduced Susceptibility to Amphotericin B

1999 ◽  
Vol 43 (11) ◽  
pp. 2592-2599 ◽  
Author(s):  
David W. Denning ◽  
Peter Warn
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Dose Range ◽  
Respiratory Arrest ◽  
Optimal Dosage ◽  
Lipid Complex ◽  
Amphotericin B Deoxycholate ◽  
Liver And Kidney ◽  
Amphotericin B Lipid Complex

ABSTRACT Using an isolate of Aspergillus fumigatus that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [P = 0.24] and 1 mg/kg [P < 0.0001]), ABLC (5 mg/kg [P = 0.014] and 1 mg/kg [P < 0.0001]), and amphotericin B deoxycholate (5 mg/kg [P = 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (P = 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [P = 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.

scholarly journals Pharmacokinetics and Pharmacodynamics of Amphotericin B Deoxycholate, Liposomal Amphotericin B, and Amphotericin B Lipid Complex in an In Vitro Model of Invasive Pulmonary Aspergillosis

2010 ◽  
Vol 54 (8) ◽  
pp. 3432-3441 ◽  
Author(s):  
Jodi M. Lestner ◽  
Susan J. Howard ◽  
Joanne Goodwin ◽  
Lea Gregson ◽  
Jayesh Majithiya ◽  
...  
Keyword(s):  
Confocal Microscopy ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Host Cells ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Amphotericin B Deoxycholate ◽  
Amphotericin B Lipid Complex

ABSTRACT The pharmacodynamic and pharmacokinetic (PK-PD) properties of amphotericin B (AmB) formulations against invasive pulmonary aspergillosis (IPA) are not well understood. We used an in vitro model of IPA to further elucidate the PK-PD of amphotericin B deoxycholate (DAmB), liposomal amphotericin B (LAmB) and amphotericin B lipid complex (ABLC). The pharmacokinetics of these formulations for endovascular fluid, endothelial cells, and alveolar cells were estimated. Pharmacodynamic relationships were defined by measuring concentrations of galactomannan in endovascular and alveolar compartments. Confocal microscopy was used to visualize fungal biomass. A mathematical model was used to calculate the area under the concentration-time curve (AUC) in each compartment and estimate the extent of drug penetration. The interaction of LAmB with host cells and hyphae was visualized using sulforhodamine B-labeled liposomes. The MICs for the pure compound and the three formulations were comparable (0.125 to 0.25 mg/liter). For all formulations, concentrations of AmB progressively declined in the endovascular fluid as the drug distributed into the cellular bilayer. Depending on the formulation, the AUCs for AmB were 10 to 300 times higher within the cells than within endovascular fluid. The concentrations producing a 50% maximal effect (EC50) in the endovascular compartment were 0.12, 1.03, and 4.41 mg/liter for DAmB, LAmB, and ABLC, respectively, whereas, the EC50 in the alveolar compartment were 0.17, 7.76, and 39.34 mg/liter, respectively. Confocal microscopy suggested that liposomes interacted directly with hyphae and host cells. The PK-PD relationships of the three most widely used formulations of AmB differ markedly within an in vitro lung model of IPA.

scholarly journals Effects of Lipid Formulations of Amphotericin B on Activity of Human Monocytes against Aspergillus fumigatus

2006 ◽  
Vol 50 (3) ◽  
pp. 868-873 ◽  
Author(s):  
J. Dotis ◽  
M. Simitsopoulou ◽  
M. Dalakiouridou ◽  
T. Konstantinou ◽  
A. Taparkou ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Colloidal Dispersion ◽  
Early Event ◽  
Human Monocytes ◽  
Xtt Assay ◽  
Lipid Complex ◽  
Production Of Hydrogen ◽  
Flow Cytometric Measurement ◽  
Lipid Formulations

ABSTRACT The immunomodulatory effects of liposomal amphotericin B (LAMB), amphotericin B lipid complex, and amphotericin B colloidal dispersion (ABCD) on antifungal activity of human monocytes (MNCs), an important component of antifungal host defense, against Aspergillus fumigatus were compared to those of deoxycholate amphotericin B (DAMB). MNCs from healthy volunteers were incubated with 1 or 5 μg/ml DAMB and 5 or 25 μg/ml lipid formulations for 22 h. Drug-pretreated or untreated MNCs were then washed and assayed for the following: (i) activity against A. fumigatus hyphae by XTT assay at MNC:hypha ratios of 10:1 and 20:1; (ii) production of superoxide anion (O2 −) from MNCs in response to hyphae by cytochrome c reduction; (iii) production of hydrogen peroxide (H2O2) and H2O2-dependent intracellular intermediates (DIIs), such as OH− and HOCl, from MNCs in response to A. fumigatus culture supernatant by flow cytometric measurement of dihydrorhodamine-1,2,3 oxidation. With the exception of 1 μg/ml DAMB and 5 μg/ml LAMB or ABCD at 10:1, all amphotericin B formulations at both concentrations and MNC:hypha ratios enhanced MNC-induced damage of A. fumigatus hyphae compared to results with untreated cells (P < 0.01). While MNC O2 − production upon hyphal challenge, an early event in oxidative burst, was not affected by the drugs, production of H2O2 and DIIs, late events, were significantly increased by all four drugs (P < 0.01). At clinically relevant concentrations, both conventional amphotericin B and its lipid formulations enhance antihyphal activity of MNCs against A. fumigatus in association with significant augmentation of H2O2 and DIIs but not O2 −, further demonstrating the immunomodulatory antifungal activities of these agents.

scholarly journals Pharmacodynamics of Amphotericin B Deoxycholate, Amphotericin B Lipid Complex, and Liposomal Amphotericin B against Aspergillus fumigatus

2015 ◽  
Vol 59 (5) ◽  
pp. 2735-2745 ◽  
Author(s):  
Zaid Al-Nakeeb ◽  
Vidmantas Petraitis ◽  
Joanne Goodwin ◽  
Ruta Petraitiene ◽  
Thomas J. Walsh ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Liposomal Amphotericin B ◽  
Complete Suppression ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Amphotericin B Deoxycholate ◽  
Amphotericin B Lipid Complex ◽  
Dose Dependent

ABSTRACTAmphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1→3)-β-d-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the “average” patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1→3)-β-d-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1→3)-β-d-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1→3)-β-d-glucan levels in the majority of patients.

scholarly journals Pulmonary Epithelial Lining Fluid Concentrations after Use of Systemic Amphotericin B Lipid Formulations

2009 ◽  
Vol 53 (11) ◽  
pp. 4934-4937 ◽  
Author(s):  
Stefan Weiler ◽  
Gerda Falkensammer ◽  
Angelika Hammerer-Lercher ◽  
Markus Anliker ◽  
Helene Vogelsinger ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Colloidal Dispersion ◽  
Standard Errors ◽  
Epithelial Lining ◽  
Lipid Complex ◽  
Epithelial Lining Fluid ◽  
Lipid Formulations

ABSTRACT Amphotericin B (AMB) concentrations were determined in pulmonary epithelial lining fluid (ELF) of 44 critically ill patients, who were receiving treatment with liposomal AMB (LAMB) (n = 11), AMB colloidal dispersion (ABCD) (n = 28), or AMB lipid complex (ABLC) (n = 5). Mean AMB levels (± standard errors of the means) in ELF amounted to 1.60 ± 0.58, 0.38 ± 0.07, and 1.29 ± 0.71 μg/ml in LAMB-, ABCD-, and ABLC-treated patients, respectively (differences are not significant).

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