Understanding antifungal prophylaxis with posaconazole in hematology patients:an evolving bedside to bench story

Abstract

Two randomized controlled clinical trials have evaluated the utility of posaconazole in antifungal prophylaxis in high-risk hematology patients.1,2 Posaconazole use was associated with a significant reduction in fungal infections and death due to invasive fungal disease in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplasia (AML/MDS)1 and those with graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation.2 The strength of these trials and subsequent real life studies3,4 led to FDA and EMA approval of posaconazole in 2007 and widespread recommendations for posaconazole use by international guidelines.1,2,5–8 The success of posaconazole prophylaxis in the registration trials appear, however, to be at odds with the finding that serum levels of posaconazole were surprisingly low in both studies (Cavg of 583 ng/mL in AML/MDS and 1103 ng/mL in GVHD).9,10 Furthermore, serum posaconazole levels were paradoxically lowest in the AML/MDS trial in which the most dramatic clinical effect was observed. Since the minimum inhibitory concentration (MIC) of posaconazole for most strains of Aspergillus fumigatus is 500 ng/mL,11 it would appear that in the AML/MDS trial essentially half the patients in this trial should have had insufficient drug exposure to offer protection against infection. This discrepancy between serum drug levels and observed efficacy has raised new questions about our understanding of the pharmacokinetics and pharmacodynamics of posaconazole in relation to its use for primary antifungal prophylaxis.