A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics

摘要

Abstract Plazomicin is an aminoglycoside with in vitro activity against multidrug‐resistant Enterobacteriaceae. A phase 1, randomized, double‐blind, crossover study assessed the potential effects of plazomicin on cardiac repolarization (NCT01514929). Fifty‐six healthy adults (24 men, 32 women) received a single therapeutic dose of plazomicin (15 mg/kg administered by 30‐minute intravenous infusion), a single supratherapeutic dose of plazomicin (20 mg/kg administered by 30‐minute intravenous infusion), placebo, or oral moxifloxacin (400 mg). The primary end point was the baseline‐adjusted, placebo‐corrected QTc interval using the Fridericia formula (ΔΔQTcF). Assay sensitivity was concluded if the lower limit of a 1‐sided 95%CI (adjusted for multiplicity using the Hochberg procedure) for moxifloxacin ΔΔQTcF was 5 milliseconds at ≥1 prespecified time points. No QT prolongation effect for plazomicin was concluded if the largest mean effect was 5 milliseconds, and the upper limit of a 2‐sided 90%CI for plazomicin ΔΔQTcF was 10?milliseconds at all time points. Assay sensitivity was demonstrated based on moxifloxacin ΔΔQTcF. No QT prolongation effect for plazomicin was concluded because the largest mean ΔΔQTcF for plazomicin was 3.5 milliseconds, and the highest upper limit was 5.6 milliseconds. No clinically relevant changes were observed in electrocardiograms. For the 15‐ and 20‐mg/kg dose levels of plazomicin, mean peak plasma concentration values were 76.0 and 96.6 mg/L, and mean values of the area under the concentration‐time curve over 24 hours were 263 and 327 mg·h/L, respectively. Model‐derived pharmacokinetic parameters and safety findings were generally consistent with previously reported plazomicin studies. In conclusion, therapeutic and supratherapeutic doses of plazomicin had no clinically significant effect on cardiac repolarization and were generally well tolerated.