Background: Isavuconazole (BAL8557/BAL4815, ISA) is a new water-soluble triazole which has broad in vitro activity against yeasts, moulds (including zygomycetes) and dermatophytes. The oral formulation is almost completely bioavailable and the i.v. formulation can be administered to renally impaired patients because it does not contain cyclodextrins. ISA is currently in phase III clinical development. This study was designed to investigate the cardiac safety of ISA at two dose levels.
Methods: A total of 80 healthy subjects received a single dose of 400 mg moxifloxacin as a positive control for prolongation of QTc, and subsequently were randomized to group A and B: Group A: Staggered oral loading doses of 400, 300 and 200 mg ISA were administered on Days 4, 5 and 6, followed by 100 mg qd ISA on Days 7 to 10, and one IV infusion of 100 mg ISA on Day 11. Three staggered oral loading doses of BAL8557 of 300, 250 and 200 mg ISA equivalents were administered on Days 12 to 14, followed by once daily oral maintenance doses of 150 mg ISA on Days 15-18, and one i.v. infusion of 150 mg ISA as a 1-hour infusion on Day 19. Group B: 40 subjects receiving placebos. Time-matched, baseline-subtracted QTc measure was used for analysis.
Results: Moxifloxacin effect was statistically significant and increased QTcF in both groups (6 ms in Group A, 7 ms in Group B) compared to baseline, as expected. During the remainder of the study period a reduction of QTcF from baseline was observed both after ISA and in the placebo control arm. Reduction of QTc from baseline was generally more pronounced in the ISA group. There was no apparent difference in QTc results between the oral or i.v. treatment phase, nor between the 100 mg steady state or 150 mg steady-state dose level. Dosing was well tolerated.
Conclusions: In contrast to the moxifloxacin positive control, no QTc increase was observed for two dosing regimen of Isavuconazole. The decrease of QTcI in comparison with placebo was slight (between 5 and 10 msec) and does not preclude of the safety of the drug.