Exposure-Safety Analysis of Isavuconazole in Patients from SECURE Study with Disease Caused by Aspergillus Species or Other Filamentous Fungi

A. Desai, L. Kovanda, D. Kowalski, R. Townsend, S. Mujais, P. Bonate;

Author address: 

Astellas Pharma, Northbrook, IL

Abstract: 

Background: 

Isavuconazole (ISAV) is a novel, water-soluble, broad-spectrum, triazole antifungal developed for the treatment of invasive fungal disease. This analysis evaluated the relationship between exposure and response (safety) for ISAV. 

Methods: 

Data from patients with proven/probable/possible invasive Aspergillus (IA) or disease caused by other filamentous fungi, who were enrolled in the SECURE (NCT00412893) Phase 3 study, were used in the analysis. The dosing regimen for this study was loading dose of 372 mg isavuconazonium sulfate (equivalent to 200 mg of ISAV) every 8 h for 6 doses (48 h) administered either by PO or IV followed by daily maintenance doses of 372 mg isavuconazonium sulfate (equivalent to 200 mg of ISAV). Liver function tests, aspartate aminotransferase (AST) and alanine transaminase (ALT) values at end of treatment (EOT) and post baseline (EOT+10 days) were used as safety markers for this analysis. AST and ALT severity was analysed as binary (>3ULN) and also as ordinal (>3 ULN; 3-5 ULN; 5-10 ULN and >10 ULN). Total area under the plasma concentration curve at steady state (AUC, calculated as dose/clearance) obtained from previously developed population PK model and simulated concentrations at steady state (Css) after 7 (C7) and 14 days (C14) of dosing were analyzed against safety endpoints using logistic regression in SAS (Version 9.3). Primary exposure parameters, as well as race, were added in an automated stepwise approach with α = 0.3 for model inclusion and α = 0.05 for model retention. Safety endpoints were analyzed in both the intent to treat population (ITT) and modified intent to treat population (mITT) population. 

Results

In total, 231 and 129 patients were part of the ITT and mITT populations, respectively. None of the primary exposure parameters or race was statistically significant for any of the safety markers in both the ITT and mITT population. 

Conclusions

No statistically significant relationships were observed for any of the exposure parameters of ISAV (AUC, Css, C7, and C14) with any liver function test safety endpoints (AST, ALT) for either the ITT or mITT populations. Lack of association between exposure and safety endpoints indicate that ISAV exposures achieved by clinical dosing were not critically elevated to cause significant adverse events.

abstract No: 

A-019
    • ICAAC 55th (2015)