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

Abstract

Amphotericin 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)-␤-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 ( Infections caused by Aspergillus fumigatus are a persistent public health problem. Diagnosis is slow and inaccurate, and there are still relatively few antifungal agents. The use of available compounds is difficult and requires specialist knowledge. The antiAspergillus triazoles (itraconazole, voriconazole, and posaconazole) and the polyenes have relatively narrow therapeutic indices (1). Suboptimal and toxic drug exposures are both potentially lethal. Both intrinsic and acquired forms of drug resistance to the triazoles are an ever-present concern (2) and are associated with a high mortality rate; in some centers, this has influenced local prescribing practices. There is an urgent requirement for the development of new antifungal compounds and a better understanding of the use of existing agents (1). Amphotericin B was first developed in 1957 (1). Despite this, there is still a relatively limited understanding of its pharmacokinetics (PK) and pharmacodynamics (PD) against A. fumigatus, and uncertainty surrounds the use of each of the formulations for the treatment of invasive pulmonary aspergillosis (IPA).Here, we provide further insight into the PD of three clinically licensed formulations of amphotericin B against A. fumigatus. Using a well-validated persistently-neutropenic-rabbit model of IPA (3), we linked concentrations of amphotericin B with levels of circulating galactomannan and (1¡3)-␤-D-glucan, both of which are licensed for the diagnosis of IPA and widely available in routine clinical microbiology laboratories. We linked the kinetics of these biomarkers with more basic measures of organism-mediated pulmonary injury (OPMI), such as lung weight and pulmonary infarct score. We describe the resultant exposure-response relationships and reflect on the adequacy of currently recommended antifungal regimens, as well as the potential limitations of fixed regimens.(This work was presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 5 t...

In Vitro and In Vivo Exposure-Effect Relationship of Liposomal Amphotericin B against Aspergillus fumigatus

“…The in vitro PK/PD index for L-AMB is higher than the corresponding index for conventional AMB (C-AMB) previously found in the same model (0.31 versus 0.15) (24), indicating that higher L-AMB than C-AMB concentrations are required for the same effect. A similar observation was found in an in vitro static model of human alveoli and in animal models, indicating that some of the active compound is locked in the liposome, rendering it inert (25,26). Interestingly, the PK/PD index of L-AMB determined in the present study (tC max /MIC, 31, taking into account the ϳ1% f u ) was similar to the PK/PD index determined in the static model (tC max /MIC, 31.04) in the alveolar compartment where conidia were inoculated and drug diffused into it from the endovascular compartment via the endothelial/alveolar cell lines.…”

Pharmacodynamics of the Orotomides against Aspergillus fumigatus : New Opportunities for Treatment of Multidrug-Resistant Fungal Disease

“…If well tolerated, the use of higher targets may result in additional antifungal activity. These target values are predicted to result in antifungal activity that matches or exceeds that induced by other licensed agents for invasive aspergillosis, such as posaconazole, isavuconazole, and liposomal amphotericin B ( 8 , 12 , 13 ).…”

Fungal diseases: could nanostructured drug delivery systems be a novel paradigm for therapy?

“…73 Approximately 50 years after the discovery of liposomes, the FDA approved 13 liposome-based products for human 80 and pulmonary aspergillosis. 81,82 However, in 2013, Ariano et al 83 reported that L-AmB may not be adequate to control lung infections by Blastomyces dermatitidis. Al Nakeeb et al 82 found that lipid formulations of AmB can induce dose-dependent reduction in lung injury markers and circulating fungal biomarkers.…”

“…81,82 However, in 2013, Ariano et al 83 reported that L-AmB may not be adequate to control lung infections by Blastomyces dermatitidis. Al Nakeeb et al 82 found that lipid formulations of AmB can induce dose-dependent reduction in lung injury markers and circulating fungal biomarkers. The recommended therapeutic dosages are 3-6 mg/kg/d.…”

“…35 A clinical dose of L-AmB 3 mg/ kg/d may cause complete suppression of both galactomannan and levels of 1,3-β-d-glucan in most patients with invasive aspergillosis. 82 The literature reports some problems associated with administration of L-AmB, such as hepatotoxicity, 84 progressive leukoencephalopathy, 85,86 and also development of lysosomal storage disease. 87 Treatment failures have also been reported.…”