Background: Lipid formulations of amphotericin B are extensively used to treat invasive pulmonary aspergillosis (IPA). However, relatively little is known about the pharmacodynamics of these compounds for IPA, nor the performance of clinically relevant biomarkers that can be used to follow antifungal therapy. Methods: A neutropenic rabbit model of IPA was studied using isolate NIH4215. DAmB was administered at 0.1, 0.5 and 1 mg/kg/d for up to 14 days. LAmB and ABLC were administered at 1, 2.5 and 5 mg/kg/d for up to 14 days. Rabbits were serially sacrificed to estimate lung weight, infarct score. The antifungal effect and pharmacodynamics were determined by serially measuring serum concentrations of galactomannan (GM) and (1[[Unable to Display Character: ]]3)-β-D-glucan (BG). Plasma concentrations of circulating drug were determined by HPLC. A linked PK-PD mathematical model was fitted to the combined PK-PD dataset obtained for each formulation and biomarker combination. The mathematical model was used to estimate the relationship between drug exposure (quantified in terms of AUC:MIC) and the decline in both GM and BG. Results: There was a progressive increase in lung weight, infarct score, GM and BG in untreated rabbits. A dosage of DAmB 1 mg/kg/d, LAmB 5 mg/kg/d, and ABLC 5 mg/kg/d was associated with maximal antifungal activity. The performance of GM and BG was comparable. The fit of each of the mathematical models to the PK-PD data for each formulation and biomarker was highly acceptable. The exposure-response relationships for DAmB and ABLC were comparable. For both formulations, half maximal effect was observed with an AUC:MIC of ~10. For LAmB, half maximal effect was observed with an AUC:MIC of ~ 75. Conclusions: All formulations produced a dose-dependent reduction in lung weight, infarct score, and circulating GM and BG concentrations. The performance of GM and BG were highly comparable and reflected changes in both lung weight and infarct score. Exposure-response relationships for DAmB and ABLC were comparable. Higher AUC:MIC values of LAmB were required to achieve reduction in fungal related biomarkers. This study can be used to provide a further insight into optimal human regimens of each formulation for treatment of IPA.
Full conference title:
- ICAAC 54th (2014)