Pharmacokinetic Evaluation of Amphotericin B in Lung Tissue: Lung Lymph Distribution after Intravenous Injection and Airspace Distribution after Aerosolization and Inhalation of Amphotericin B

Abstract

We have studied the pharmacokinetics of amphotericin B (AmB) in lung lymph circulation and bronchial-wash fluid after intravenous infusion and inhalation, respectively. For two experiments with awake sheep, we used lung lymph fistulas and tracheotomy. In experiment 1, AmB concentrations in plasma and lung lymph after intravenous infusion of AmB (1 mg/kg of body weight) over 1.5 h were measured. The mean peak in plasma level was 756.0 ± 188.8 ng/ml at 3 h after the start of infusion, and the level then decreased gradually to 194.8 ± 28.9 ng/ml at 24 h. The stable and maximal levels in lung lymph last 5 to 9 h after the start of AmB infusion. The concentrations in lung lymph after 9 h were slightly higher than those in plasma. Thus, the lung lymph-to-plasma ratio of AmB concentrations increased gradually during infusion, and the ratio was more than 1.0 after the end of infusion, suggesting that AmB could be easily moved from plasma to pulmonary interstitium and/or lung lymph circulation. In another experiment, 5 or 30 mg of aerosol AmB was inhaled, and the concentration of AmB in the bronchial-wash fluid was determined by bronchoalveolar lavage. The peak AmB concentration in the fluid was observed at 0.5 h. After that, AmB was slowly eliminated over 24 h. The area under the concentration-time curve for 30 mg of inhaled AmB was higher than that for 5 mg, but maximum concentrations of AmB in serum for 5 and 30 mg were almost similar. These observations identify the pharmacokinetic characteristics of AmB in the lung and may provide a new insight into the strategy for clinical treatment of fungal pneumonia.

Use of Aerosolized Antifungals for the Prophylaxis Against and Treatment of Invasive Pulmonary Aspergillosis: Climbing it because it is there?

“…From a pharmacokinetic perspective, inhalation of amphotericin B results in rapid attainment of therapeutic concentrations in epithelial lining fluid which remain above 1µg/ml for more than 7 days following inhalation [12]. This characteristic is in contrast to data observed following intravenous administration which demonstrate delayed distribution to the pulmonary tissues and appreciably lower drug concentrations [14].…”

“…The safety and intrapulmonary distribution characteristics of various formulations of amphotericin B have been studied in various animal models, healthy subjects and patient populations [20,12,14,17,5,13,7]. Deoxycholate formulations of amphotericin B have been found to increase the surface tension of the natural surfactant found in the lung which might result in impaired pulmonary function [6,17] and lipid-based formulations did not exhibit this effect [17].…”

Aerosolized Delivery of Antifungal Agents

“…In addition, the use of RespirGard II (Marquest; Englewood, CO) and PariBoy or Pari IS II (both Pari Werke; Starnberg, Germany) for nebulization of AmBd has been shown to generate particles that deposit in the alveoli, trachea, and nasopharynx [27]. Based on a pharmacokinetic study in sheep, the maximum intrapulmonary concentration was not influenced by the dose (5 mg vs 30 mg) [28]. However, the area under the concentration-time curve was greater for the larger dose.…”

Inhaled therapeutics for prevention and treatment of pneumonia

“…Pre-infection ABLC treatment with 0.4 – 1.6 mg/kg given 2 days before infection provided a 63 – 100% survival benefit in animal experiments [148]. The peak concentration of amphotericin B in bronchioalveolar lavage after a single dose occurs 30 min after inhalation, and it is slowly cleared from the lungs over the next 24 h [149]. …”

“…Occasionally, in patients with T-cell immune defects hMPV has been show to cause disseminated fatal disease [149]. In patients with stem cell or solid-organ transplantation these infection, even with limited pulmonary disease, are life threatening and increase risk for post-viral invasive fungal pneumonia [150].…”