Pharmacodynamics of Isavuconazole in a Rabbit Model of Cryptococcal Meningoencephalitis

Abstract

Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis.

Keywords: Cryptococcus neoformans; cryptococcosis; fluconazole; isavuconazole; isavuconazonium sulfate; meningoencephalitis.

FIG 1

Changes in fungal burden in the rabbit brain (a) and CSF (b). (a) Fungal burden in brain. All treatment groups (isavuconazonium sulfate at 83.8 mg/kg and 111.8 mg/kg and fluconazole at 80 mg/kg) resulted in significant reductions in the number of log₁₀ CFU per gram in the brain at the end of treatment compared with that in the brains of untreated rabbits (P = 0.0003, P = 0.0002, and P = 0.0034, respectively, one-way ANOVA, Holm-Šidák’s multiple-comparison test). There was no statistically significant difference between either isavuconazonium sulfate treatment group versus the fluconazole treatment group (P > 0.05). (b) Fungal burden in CSF. Significant changes in the number of log₁₀ CFU per milliliter over time in CSF were demonstrated for all treatment groups (isavuconazonium sulfate at 83.8 mg/kg and 111.8 mg/kg and fluconazole at 80 mg/kg) versus that in the CSF of untreated rabbits (P < 0.0001, Tukey’s multiple-comparison test). Note that not all animals survived to day 14. CSF, cerebrospinal fluid; ISAV, isavuconazonium sulfate; FLU, fluconazole.

FIG 2

(a) Observed versus median posterior predicted isavuconazole plasma concentrations (in milligrams per liter) from the final model after the Bayesian step (r² = 0.841, slope = 0.951 [95% confidence interval = 0.853 to 1.050], intercept = 0.366 [95% CI = −0.018 to 0.751]). (b) Observed versus median posterior predicted isavuconazole CSF concentrations (in milligrams per liter) from the final model after the Bayesian step (r² = 0.745, slope = 0.958 [95% confidence interval = 0.79 to 1.13], intercept = 0.00198 [95% confidence interval = −0.00617 to 0.01010]). (c) Observed versus median posterior predicted number of log₁₀ CFU per milliliter of CSF from the final model after the Bayesian step (r² = 0.692, slope = 0.853 [95% CI = 0.69 to 1.02], intercept = 0.577 [95% confidence interval = −0.0697 to 1.22]). The dashed lines are the line of unity, where the observed concentration equals the predicted concentration. CSF, cerebrospinal fluid.