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

Abstract

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.

Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

“…However, in our previous studies with azoles, we showed that using survival as a gold standard endpoint in our model provides useful exposure-response relationships. Studies with azoles in neutropenic (27,47,48) and nonneutropenic (23,49,50) models have shown that the exposure-response relationships are of the same order of magnitude; in fact, a slightly lower drug exposure target may be required in the neutropenic model. This could possibly be because of the lower inoculum used in this model.…”

“…There are only limited preclinical data on the in vivo efficacy of isavuconazole in azole-resistant IA (27). Therefore, the objective of the present study was to investigate the pharmacodynamics (PD) and dose-response and exposure-response relationships of isavuconazole against wild-type and clinical azole-resistant A. fumigatus isolates harboring different substitutions in the Cyp51A gene in an immunocompetent murine model of disseminated aspergillosis.…”

Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

“…However, there is a paucity of laboratory animal data for isavuconazole against Aspergillus spp. The pharmacodynamics of isavuconazole was explored in a murine neutropenic IPA model by Lepak and colleagues (15) and also in an invasive aspergillosis model of immunocompetent mice by Seyedmousavi et al (16). We therefore studied the efficacy and pharmacokinetics of isavuconazole in treatment of experimental IPA in persistently neutropenic rabbits.…”

A Phase 2, Randomized, Double-Blind, Multicenter Trial To Evaluate the Safety and Efficacy of Three Dosing Regimens of Isavuconazole Compared with Fluconazole in Patients with Uncomplicated Esophageal Candidiasis

“…including Candida spp., Aspergillus spp., Cryptococcus spp., and mucormycetes (16)(17)(18)(19). The results of animal model studies have also shown that isavuconazole is effective in the treatment of invasive candidiasis, invasive aspergillosis, and mucormycosis (15,(20)(21)(22)(23). Moreover, in a recent phase 2 study, isavuconazole was shown to be well tolerated as prophylaxis in neutropenic patients with acute myeloid leukemia (31).…”