Compartmentalized Intrapulmonary Pharmacokinetics of Amphotericin B and Its Lipid Formulations

Abstract

Invasive mycoses of the lung caused by opportunistic filamentous fungi, such as Aspergillus spp., Zygomycetes, Fusarium spp., and Scedosporium spp., are frequent and often cause fatal infections in immunocompromised patients, particularly those with cancer and those who have undergone hematopoietic stem cell transplantation. Despite the emergence of novel antifungal triazoles and echinocandin lipopeptides, amphotericin B and its lipid formulations remain important options for empirical antifungal therapy for patients at the highest risk and for the treatment of probable and proven infections (13).The four licensed formulations of amphotericin B have different physicochemical characteristics that result in distinct plasma pharmacokinetics (14,27,30). However, whether and to what extent these different dispositions of amphotericin B in plasma lead to different disposition patterns in distinct compartments of the lung are largely unknown.The purposes of the present experimental studies, therefore, were to investigate the comparative intrapulmonary dispositions of the four licensed amphotericin B formulations in epithelial lining fluid (ELF), pulmonary alveolar macrophages (PAM), and total lung tissue and to relate these concentration data to their disposition in peripheral blood monocytes (PBM) and plasma. MATERIALS AND METHODSStudy drug. Deoxycholate amphotericin B (DAMB) was prepared from commercially available amphotericin B (Fungizone; Bristol-Myers Squibb, Princeton, NJ); the initial powder was dissolved with sterile water and then further diluted with 5% dextrose in water, as recommended, to a final concentration of 1 mg/ml. Amphotericin B colloidal dispersion (ABCD) (Amphotec; Intermune, Brisbane, CA) was provided as lyophilized sterile powder (100 mg/vial). Prior to its use, the powder was dissolved in 20 ml of sterile water and then further diluted with 5% dextrose in water to a final concentration of 1 mg/ml. Amphotericin B lipid complex (ABLC) (Abelcet; Enzon Pharmaceuticals, Bridgewater, NJ) was provided as a 5-mg/ml solution in 20-ml vials and further diluted to a 1-mg/ml solution with 5% dextrose in water prior to use. Liposomal amphotericin B (LAMB) (AmBisome; Fujisawa USA, Deerfield, IL) was prepared from lyophilized powder. The powder was initially reconstituted with 12 ml of sterile water, shaken vigorously for 30 seconds, filtered through a 5-m filter, and further diluted with 5% dextrose in water to a final concentration of 1 mg/ml. All drugs were freshly prepared prior to use.Animals. Healthy female New Zealand White rabbits (Oryctolagus cuniculus; Hazleton, Denver, PA) weighing 2.5 to 3.5 kg were used in all experiments. They were individually housed and maintained with water and standard autoclaved rabbit feed ad libitum according to National Institutes of Health (NIH) Guide-* Corresponding author. Mailing address: CRC-1-5750,

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

“…Consequently, it is somewhat surprising that relatively little is known about the pharmacology, PK, and PD of this compound against IPA. The PK-PD relationships of amphotericin B have been difficult to elucidate because of complex properties of binding to low-and high-density lipoproteins, as well as to plasma proteins (11), notoriously steep exposureresponse relationships (4, 12), a narrow therapeutic index (13), significant idiosyncrasies in the PK and PD properties that are imparted by the formulation (12,14,15), and complex intrapulmonary distributions (16).…”

“…The amphotericin B lipid formulations remain especially valuable because of the progressive emergence of triazole resistance in many parts of the world and because of triazole-related adverse events. A regimen of LAMB at 3 mg/kg/day is usually used for the treatment of A. fumigatus and is ultimately based on laboratory animal studies (3) and multiple clinical trials that have attempted to define safe and effective regimens (15)(16)(17). Early clinical studies examined regimens as high as 15 mg/kg/day to test the hypothesis that the dosing of DAMB was suboptimal because of dose-limiting toxicity (21,22).…”

Comparative Pharmacodynamics of Amphotericin B Lipid Complex and Liposomal Amphotericin B in a Murine Model of Pulmonary Mucormycosis

“…Hence, the intravenous administration of L-AMB results in sustained, high concentrations of encapsulated AMB in the bloodstream and a somewhat delayed distribution of free drug into tissue. Conversely, the intravenous administration of the larger-particle ABLC formulation (1,600 to 11,000 nm) results in relatively lower AMB bloodstream concentrations due to the rapid uptake and distribution to tissues rich in mononuclear phagocytic cells, including lung tissue (9,18,19). The clinical relevance of these pharmacokinetic differences between L-AMB and ABLC, however, remains unknown.…”

Tissue Penetration of Antifungal Agents

“…Furthermore, the biological relevance of the total concentrations associated with each formulation is also unclear. Human data for the various amphotericin formulations suggest that there may be some differences compared with rabbits (146,147). Thus, intravenous ABLC produces ELF amphotericin B concentrations that are approximately 4 times those produced after administration of L-AMB in humans (147).…”