Pharmacodynamics and Pharmacokinetics of Antifungals for Treatment of Invasive Aspergillosis

Romuald      Bellmann

Abstract

Amphotericin B has been the only therapeutic option for invasive aspergillosis over decades. It acts by binding to membrane ergosterol, lipid peroxidation and proton-ATPase inhibition. Amphotericin B is eliminated unchanged via urine and feces. It displays a considerable toxicity, particularly infusion-related adverse events and renal damage. Continuous infusion and administration of lipidformulations of amphotericin B are strategies to improve its tolerability. Amphotericin B has a post-antifungal effect (PAFE), and its peak concentration is probably crucial for its fungicidal efficacy. The amphotericin B lipid-formulations display largely different pharmacokinetics. Kinetics of amphotericin B which is liberated from its lipid encapsulation in the plasma is similar for all three available lipid formulations. Azoles inhibit the synthesis of fungal cell membrane ergosterol. The triazoles itraconazole, voriconazole and posaconazole are active against Aspergilli. Voriconazole is the drug of choice for therapy of invasive aspergillosis. It is metabolized in the liver and metabolites are excreted via the kidneys. Posaconazole is licensed for antifungal prophylaxis in hematological high-risk patients and for salvage therapy of invasive aspergillosis. A variety of drug-drug interactions have to be considered with all azoles. The ratio between the area under the time-concentration profile (AUC) and the minimal inhibitory concentration (MIC) is the relevant pharmacokinetic/ pharmacodynamic parameter for azoles. Caspofungin the only echinocandin licensed for second line therapy of invasive aspergillosis is fungistatic to Aspergilli displaying a paradoxical pharmacodynamic effect. Caspofungin elimination is independent from renal function. Although it is metabolized in the liver its potential for drug interactions is moderate.

Keywords: Polenes, amphotericin B lipid formulations, liposomal amphotericin B, amphotericin B cholesteryl sulphate, amphotericin B colloidal dispersion, amphotericin B lipid complex, itraconazole, voriconazole, echinocandins, caspofungin.