Background: Isavuconazole is an extended-spectrum azole currently under investigation in Phase 3 studies in subjects with systemic fungal infection. Isavuconazole is slowly eliminated by CYP-mediated clearance. Previous PK results in liver impairment due to alcohol abuse were presented at ICAAC last year (Poster A-007). The present study investigates the fate of Isavuconazole in liver impairment caused by hepatitis B and C.
Methods: Healthy male and female subjects and subjects (n=8/group) with mild and moderate liver impairment received a single 2-h i.v. or an oral dose of the prodrug equivalent to 100 mg Isavuconazole. Pharmacokinetic parameters were derived using WinNonlin 5.2.1. ANOVA was used to assess the statistical significance of differences in Isavuconazole PK.
Results: Average Child-Pugh score of 5.9 and 8.4 was measured in subjects with mild and moderate liver impairment due to hepatitis, respectively.
Liver disease resulted in a decrease of the systemic clearance (CL) of Isavuconazole accompanied by approximately a two-fold increase in half-life. The AUC was almost doubled in moderate impairment. Statistically the AUC was different in liver impaired subjects when compared to healthy volunteers. Cmax was slightly but not significantly decreased in liver impaired subjects. Isavuconazole was well tolerated in healthy and liver impaired subjects. Similar results were observed in liver impairment due to alcohol abuse.
Conclusion: Irrespective of the origin of liver impairment (alcohol abuse or hepatitis), administration of Isavuconazole to subjects with mild or moderate liver impairment will require a similar dose adjustment compared to healthy subjects.
- ICAAC 49th