Impact of dose fractionation on the in vivo efficacy of isavuconazole in a murine model of Aspergillus fumigatus infection

Seyedmousavi, Seyedmojtaba; Brüggemann, Roger J.M.; Meis, Jacques F.; Melchers, Willem. J. G.; Verweij, Paul E.; Mouton, Johan W.


Isavuconazole is an investigational broad-spectrum triazole currently being investigated in the phase III clinical studies for the treatment of
severe invasive fungal infections, including invasive aspergillosis (IA). Dose fractionation studies need to explore which pharmacokinetic/
pharmacodynamic (PK/PD) index correlates best with efficacy, and to determine whether the magnitude of the PK/PD index needed for
efficacy varies among various dosing intervals.
The in vivo efficacy of q24 (once daily), q12 (fractionated into two doses) and q8 (fractioned into three doses) of 0.25, 1, 4, 16, 64, 128, 256
and 512 mg/kg/day prodrug isavuconazonium sulfate (BAL8557) (ISA-equivalent doses of 0.12, 0.48, 1.92, 7.68, 30.7, 61.4, 122.9 and 245.8
mg/kg/day, respectively) was assessed in an immunocompetent murine model of IA, against a clinical A. fumigatus isolates isolate (ISA
MICEUCAST, 0.5 mg/L). Mice were treated orally for 14 days. In addition, ISA concentrations in plasma were assayed in a separate
pharmacokinetic (PK) study at 10 predefined time points (3 mice per group) post challenge by a validated UPLC method.
The survival curves, dose-response curves, as well as the exposure-response curves were not significantly different with various dosing
intervals (P > 0.05). The survival curves for all control groups receiving saline by oral gavage, showed a mortality of 100%. The maximum
effect (100% survival) was reached at a pro-dose of 64 mg/kg. The Hill-type model with a variable slope fitted the relationship between the
area under the plasma concentration-time curve (AUC) and 14-day survival well, with R2 values of 1 (q24), 1 (q12) and 0.99 (q8),
respectively. The 50% effective AUC (ED50) was 12.05 mg·h/liter for the q24, 14.07 mg·h/liter for the q12, and 8.74 mg·h/liter for the q8
treatment. AUC0-24/MIC appeared to be the most reliable pharmacodynamic index correlating with efficacy. For a survival of 50%, the
effective AUC0-24/MIC ratio for isavuconazole total drug was 24.73 (95% confidence interval, 22.50 to 27.18).
The efficacy of isavuconazole depended on the total amount of drug (AUC), independently of the dosing interval. There was no significant
differences between exposure-response relationships of the groups treated with various dosing intervals. The quantitative relationship
between exposure and effect (AUC0-24/MIC) can be used to optimize the treatment of human infections by A.fumigatus, including strains
with decreased susceptibility.


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