A pharmacokinetic fairy tale: Goldilocks and the three azoles

D. Sheppard

Author address: 

McGill University, Montreal, Canada


The mold active azoles posaconazole, voriconazole and isavuconazole are all highly active against Aspergillus fumigatus, with varying activity against rare molds. Despite their similarity in efficacy against A. fumigatus, these agents exhibit differences in lipid solubility. Studies from our group and others have suggested that differences in hydrophobicity may result in important differences in intracellular pharmacokinetics and pharmacodynamics of antifungal agents and that these differences in intracellular concentration of antifungals may underlie differences in efficacy in prophylaxis. We therefore directly compared the ability of these three azole antifungals to concentrate in human epithelial cells and neutrophils, as well as the effects of the presence of human cells on in vitro antifungal activity of these agents against A. fumigatus. Each of the three anti-mold active azoles exhibited a unique profile of intracellular pharmacokinetics and dynamics. Voriconazole did not concentrate to any significant degree within human cells, and the antifungal activity of this agent against A. fumigatus was unaffected by the presence of host cells in co-culture. In contrast, posaconazole concentrated to high levels with both epithelial cells and human neutrophils. The increased local concentration of posaconazole within cells resulted in augmented antifungal activity of posaconazole against A. fumigatus when cells were present as compared with the identical concentration of free drug. The active metabolite of isavuconazole also concentrated within cells, although to a lesser extent than was seen with posaconazole. Interestingly, despite the ability of isavuconazole to concentrate within host cells, the presence of neutrophils or epithelial cells in co-culture was associated with a reduced level of antifungal activity against A. fumigatus in vitro as compared with free drug. This loss of antifungal activity of isavuconazole in the presence of human cells was due to intracellular metabolism of this agent by cellular cytochrome p450 (CYP) enzymes. Treatement of neutrophils with the CYP enzyme inhibitor ketoconazole restored the antifungal activity of isavuconazole. Collectively, these findings reveal important differences in intracellular pharmacokinetics between these agents. These differences should be considered in interpreting the results of serum therapeutic drug monitoring and may have important implications in the use of these agents for antifungal prophylaxis. 


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Full conference title: 

8th Trends in Medical Mycology, Organised under the auspices of EORTC-IDG and ECMM, 6-9 October 2017, Belgrade, Serbia
    • TIMM 8th (2017)