Background: Isavuconazole is an extended-spectrum azole administered orally or intra venously as a water-soluble pro-drug (WSA). Isavuconazole is currently under investigation in phase 3 studies in patients with systemic candidiasis, aspergillosis or invasive fungal infection with rare moulds. Isavuconazole is slowly eliminated by CYP-mediated clearance. Therefore, we investigated the oral PK of Isavuconazole in subjects with hepatic impairment due to alcohol consumption.
Methods: Healthy volunteers and subjects with mild and moderate liver impairment received a single oral dose of WSA equivalent to 100 mg Isavuconazole. Subjects were enrolled in three groups (n=8) matched for age, gender, body weight and BMI. Pharmacokinetic parameters were derived using WinNonlin 5.1. The Tuckey test was used to assess the statistical significance of differences in Isavuconazole pharmacokinetics.
Results: Average Child-Pugh scores of 5.2 and 7.6 were measured in subjects with mild and moderate hepatic impairment, respectively.
Subjects with liver impairment had significantly lower systemic clearance (CL/F) of Isavuconazole, compared with healthy subjects, accompanied by almost a two-fold increase in the half-life and the AUC (p<0.05). Cmax was slightly decreased in patients corresponding to a modest increase of V/F (p> 0.05). A similar effect was observed after intravenous administration (ICAAC 2008, Poster A-007). The impact of liver impairment was not statistically different to results after intravenous administration shown previously or gender.
Conclusion: Administration of Isavuconazole to patients with mild or moderate hepatic impairment will require a dose adjustment compared to normal patients. The dose adjustment will be the same irrespective of the route of administration and the gender.
- ECCMID 19th (2009)