Isavuconazole (BAL4815) Pharmacodynamic Target Determination in an In Vivo Murine Model of Invasive Pulmonary Aspergillosis against Wild-Type and cyp51 Mutant Isolates of Aspergillus fumigatus

Invasive pulmonary aspergillosis (IPA) continues to rise in concert with increasing numbers of immune suppression techniques to treat other medical conditions and transplantation. Despite these advances, morbidity and mortality rates remain unacceptably high. One strategy used to optimize outcomes is antifungal pharmacodynamic (PD) examination. We explored the pharmacodynamics of a new triazole in development, isavuconazole, in a murine neutropenic IPA model. Ten A. fumigatus isolates were used, including four wild-type isolates and six cyp51 mutants. The MIC range was 0.125 to 8 mg/liter. Following infection, groups of mice were treated orally with the prodrug (BAL8557) at 40 to 640 mg/kg/12 h for 7 days. Efficacy was determined by quantitative PCR of lung homogenates. At the start of therapy, mice had 4.97 log(10) conidial equivalents (CE)/ml of lung homogenate, and this increased to 6.82 log(10) CE/ml of lung homogenate in untreated animals. The infection model was uniformly lethal in untreated control mice. The PD target endpoints examined included the static-dose AUC/MIC ratio and the 1-log(10) killing AUC/MIC ratio. A stasis endpoint was achieved for all isolates with an MIC of <= 1 mg/liter and 1-log(10) killing in all isolates with an MIC of <= 0.5 mg/liter, regardless of the presence or absence of the cyp51 mutation. The static-dose range was 65 to 617 mg/ kg/12 h. The corresponding median free-drug AUC/MIC ratio was near 5. The 1-log(10) killing dose range was 147 to 455 mg/kg/12 h, and the corresponding median free-drug AUC/MIC ratio was 11.1. These values are similar to those previously reported for other triazoles.