International Conference on Harmonisation. Center for Biologics Evaluation and Research. Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience. Drug-induced prolongation of the QT interval. Independent Academic Task Force Drug-induced torsades de pointes and implications for drug development. Although Koreans appeared to be more sensitive to moxifloxacin-induced QT prolongation than were Caucasians, the PK-PD model developed suggests that a 400 mg dose of moxifloxacin is also applicable to QT studies in Korean subjects.Įmax model NONMEM PK-PD model thorough QT study.įenichel RR, Malik M, Antzelevitch C, et al.
The effect of moxifloxacin on QT interval prolongation was well explained by the nonlinear dose-response (Emax) model, and the effect by 800 mg was only slightly greater than that of 400 mg. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian variation of QT intervals was described by two mixed-effect cosine functions.
A two-compartment linear model with first-order absorption provided the best description of moxifloxacin PK. The PK-PD data obtained were analyzed using a nonlinear mixed-effects method (NONMEM ver. Peripheral blood samples were also obtained for PK analysis. Twelve-lead electrocardiograms were taken for 2 consecutive days: 1 day to record diurnal changes and the next day to record moxifloxacin or placebo effects. Data from three TQT studies of 33 healthy male Korean subjects who received 400 and 800 mg of moxifloxacin and placebo (water) were used. Thus, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model for moxifloxacin, to evaluate the time course of its effect on QT intervals in Koreans. However, it is not clearly known whether a 400 mg dose is also applicable to TQT studies in Asian subjects, including Koreans. A single 400 mg dose of moxifloxacin has been the standard positive control for thorough QT (TQT) studies.
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