Nebulized Liposomal Amphotericin B Prophylaxis for Aspergillus Infection in Lung Transplantation: Pharmacokinetics and Safety

doi:10.1016/j.healun.2008.11.004

The Journal of Heart and Lung Transplantation

Volume 28, Issue 2, February 2009, Pages 170-175

https://doi.org/10.1016/j.healun.2008.11.004 Get rights and content

Background

The main problem with using nebulized liposomal amphotericin (n-LAB) as prophylaxis for Aspergillus infection after lung transplantation is the lack of knowledge of its pharmacokinetics and its possible adverse effects. The aim of this study was to measure post-inhalation amphotericin B concentration in the respiratory tract and serum of lung transplant patients and assess the effects of n-LAB on respiratory function.

Methods

Thirty-two consecutive bronchoscopies were performed on 27 lung transplant patients at two hospitals. Amphotericin B concentration in the first and third aliquot of bronchoalveolar lavage material was measured in steady state. The first aliquot approximates most closely the true amphotericin B concentrations in the proximal airway, whereas the third aliquot provides an optimum sample from the distal airway.

Results

At 2 days, mean amphotericin B concentrations were 11.1 μg/ml (95% confidence interval [CI]: 16.5 to 5.7 μg/ml) and 9.0 μg/ml (95% CI: 14.3 to 3.8 μg/ml) in the first and third aliquot, respectively. Thereafter, concentrations declined progressively. At 14 days, concentrations were 3.0 μg/ml (95% CI: 4.4 to 1.5 μg/ml) in the first aliquot and 4.1 μg/ml (95% CI: 6.1 to 2.1 μg/ml) in the third aliquot (p = not statistically significant). Traces of amphotericin B (0.1 μg/ml) were found in serum samples from only 1 of 27 patients. Mean value of forced expiratory volume in the first second (FEV₁) was similar before and after n-LAB.

Conclusions

Amphotericin B concentrations after n-LAB remained high for 14 days, at adequate concentrations for prophylaxis of Aspergillus infection. No significant systemic absorption of amphotericin B was detected and no effect was observed on respiratory function. This promising prophylactic regimen warrants assessment in future clinical studies.

Section snippets

Patients and Study Design

Because of an insufficient supply of amphotericin B deoxycholate on the Spanish market, nebulized amphotericin B deoxycholate was switched to n-LAB as prophylaxis for Aspergillus infection in all lung transplant patients at our hospital, starting in June 2003. The dose of n-LAB administered was based on the results of our previous pilot study.²³ Patients received 25 mg (6 ml) 3 times per week up to Day 60 post-transplantation, 25 mg once per week between Days 60 and 180, and 25 mg once every 2

Results

Mean fluid volume recovered in the 32 samples was 26.1 ml (range 6 to 25 ml) and 34.3 ml (range: 15 to 50 ml) in the first and third BAL aliquot, respectively. Mean amphotericin B concentrations in the first and third aliquot at each time-point are shown in Figure 1. At 2 days, mean amphotericin B concentrations were 11.1 μg/ml (95% CI: 16.5 to 5.7 μg/ml) in the first aliquot and 9.0 μg/ml (95% CI: 14.3 to 3.8 μg/ml) in the third aliquot. Thereafter, concentrations decreased progressively. At 7

Discussion

To our knowledge, this is the first study investigating amphotericin B concentrations in the respiratory tract of lung transplant patients receiving nebulized liposomal amphotericin B prophylaxis. We found that amphotericin B concentrations are high enough after nebulized inhalation to inhibit the growth of most Aspergillus species, with persistently elevated levels even 14 days after administration. Moreover, the safety of the drug proved to be excellent, with virtually no systemic absorption

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Safety and usefulness of nebulized liposomal amphotericin B: Systematic scoping review
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Invasive fungal infections potentially result in fatal outcomes in immunocompromised hosts. Compared to intravenous administration, a nebulization therapy can achieve a high concentration of drug delivered in the respiratory tract, without a systematic absorption. We herein summarized the study findings on the safety and clinical utility of nebulized liposomal amphotericin B therapy.
According to the PRISMA Extension for Scoping Reviews, we performed a search on MEDLINE and EMBASE for articles with relevant keywords, including “inhaled liposomal amphotericin B″, “nebulized liposomal amphotericin B″, or “aerosolized liposomal amphotericin B″, from the inception of these databases to August 31, 2022.
Of the 172 articles found, 27 articles, including 13 case reports, 11 observational studies, and 3 clinical trials, were selected. Generally, findings showed that nebulized liposomal amphotericin B treatment appeared to be safe and without severe adverse effects. We found an accumulated evidence for the safety, tolerability, and effectiveness of nebulized liposomal amphotericin B prophylaxis among lung transplantation recipients; however, a randomized controlled study has yet to be reported. Data on hemato-oncological patients are relatively scarce; however, a randomized controlled study suggested the prophylactic effect of nebulized liposomal amphotericin B on invasive pulmonary aspergillosis. Observational and randomized controlled studies to evaluate therapeutic efficacy of the nebulized liposomal amphotericin B therapy have not been performed.
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Electron paramagnetic resonance (EPR) spectroscopy of spin labels was used to study the interactions of amphotericin B (AmB) with the plasma membrane of Leishmania (L.) amazonensis promastigotes, human erythrocytes and J774.A1 murine macrophages, in comparison with reported and novel data for miltefosine (MIL). One of the objectives of this work is to look for the relationships between the activities of these two drugs in the Leishmania parasite with their changes in the cell membrane. A spin-labeled stearic acid inserted into the cell membranes showed strong interactions with putative AmB/sterol complexes, characterized by reductions in molecular dynamics. The concentration of the drugs in the plasma membrane that reduced the cell population by 50%, and the membrane-water partition coefficient of the drugs, were assessed. These biophysical parameters enabled estimates of possible therapeutic concentrations of these two drugs in the interstitial fluids of the tissues to be made. AmB displayed higher affinity for the plasma membrane of L. amazonensis than for that of the macrophage and erythrocyte, denoting a preference for a membrane that contains ergosterol. AmB also demonstrated higher hemolytic potential than MIL for measurements on erythrocytes in both PBS and whole blood. For MIL, the EPR technique detected membrane changes induced by the drug in the same concentration range that inhibited the growth of parasites, but in the case of AmB, an 8-fold higher concentration of the IC₅₀ was necessary to observe a reduction in membrane fluidity, suggesting a better localized effect of AmB on the membrane. Taken together, the results demonstrate that the antiproliferative and cytotoxic effects of both drugs are associated with changes in cell membranes.
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Citation Excerpt :
In some studies, inhaled AmB doses up to 100 mg/day were well tolerated for at least four days [11], and nebulized AmB as a prophylaxis following lung transplantation was safely continued for life in 412 people for up to five years [28]. The broad use of inhaled AmB as an effective antifungal therapy against Aspergillus infections as well as a study which determined that AmB concentrations of at least 3.25 µM were retained in the airways at least 14 days following a single administration suggest that AmB concentrations of at least 1 µM have been safely achieved and sustained in the airways following inhalation [27]. In this study, we found that 1 µM AmB caused electrophysiological effects consistent with anion secretion in cultures of CuFi-1 epithelia, and we calculated that ASL AmB concentrations less than 1 µM similarly increased ASL pH in cultures of CuFi-1 epithelia maintained at an air-liquid interface.
Approximately 10% of people with cystic fibrosis (CF) have mutations that result in little to no CFTR production and thus cannot benefit from CFTR modulators. We previously found that Amphotericin B (AmB), a small molecule that forms anion channels, restored HCO₃⁻ secretion and increased host defenses in primary cultures of CF airway epithelia. Further, AmB increased ASL pH in CFTR-null pigs, suggesting an alternative CFTR-independent approach to achieve gain-of-function. However, it remains unclear whether this approach can be effective in people.
To determine whether AmB can impact physiology in people with CF, we first tested whether Fungizone, a clinically approved AmB formulation, could cause electrophysiological effects consistent with anion secretion in primary cultures of CF airway epithelia. We then evaluated the capacity of AmB to change nasal potential difference (NPD), a key clinical biomarker, in people with CF not on CFTR modulators.
AmB increased transepithelial Cl⁻ current and hyperpolarized calculated transepithelial voltage in primary cultures of CF airway epithelia from people with two nonsense mutations. In eight people with CF not on CFTR modulators, intranasal Fungizone treatment caused a statistically significant change in NPD. This change was similar in direction and magnitude to the effect of ivacaftor in people with a G551D mutation.
Our results provide the first evidence that AmB can impact a clinical biomarker in people with CF. These results encourage additional clinical studies in people with CF to determine whether small molecule anion channels can provide benefit.
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Transplantation infectionNebulized Liposomal Amphotericin B Prophylaxis for Aspergillus Infection in Lung Transplantation: Pharmacokinetics and Safety

Background

Methods

Results

Conclusions

Section snippets

Patients and Study Design

Results

Discussion

J Heart Lung Transplant

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J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

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J Heart Lung Transplant

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Chest

Transplant Proc

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J Chromatogr A

Transplantation infection
Nebulized Liposomal Amphotericin B Prophylaxis for Aspergillus Infection in Lung Transplantation: Pharmacokinetics and Safety