Effects of moxifloxacin on the proarrhythmic surrogate markers in healthy Filipino subjects: Exposure-response modeling using ECG data of thorough QT/QTc study

• Main Authors: Suchitra Matsukura (Author), Yuji Nakamura (Author), Kiyotaka Hoshiai (Author), Takashi Hayashi (Author), Tadashi Koga (Author), Ai Goto (Author), Koki Chiba (Author), Nur Jaharat Lubna (Author), Mihoko Hagiwara-Nagasawa (Author), Hiroko Izumi-Nakaseko (Author), Kentaro Ando (Author), Atsuhiko T. Naito (Author), Atsushi Sugiyama (Author)
• Format: Book
• Published: Elsevier, 2018-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Effects of moxifloxacin on QTc as well as proarrhythmic surrogate markers including J-Tpeakc, Tpeak-Tend and short-term variability (STV) of repolarization were examined by using both standard E14 time-based evaluation and exposure-response modeling. The study was conducted with a single-blind, randomized, single-dose, placebo-controlled and two-period cross-over design in healthy Filipino subjects. QT interval was corrected by Fridericia's formula (QTcF). In the E14 time-based evaluation of ECG data, the largest ΔΔQTcF with 90% confidence interval was 14.1 ms (11.2-16.9) with Cmax of 3.39 μg/mL at 3 h post-dose (n = 69; male: 35, female: 34), indicating a positive effect on the QTcF. Moxifloxacin significantly increased the ΔΔJ-Tpeakc and ΔΔTpeak-Tend, whereas the ΔΔSTV was not altered. Meanwhile in the exposure-response modeling of the same ECG data, the slope of moxifloxacin plasma concentration-ΔΔQTcF relationship was 4.84 ms per μg/mL and the predicted ΔΔQTcF with 90% confidence interval was 13.8 ms (13.1-15.1) at Cmax, also indicating a positive effect on the QTcF. Importantly, results in each proarrhythmic surrogate marker obtained by the exposure-response modeling also showed high similarity to those obtained by the E14 statistical evaluation. Thus, these results of moxifloxacin may become a guide to estimate proarrhythmic potential of new chemical entities. Keywords: ICH E14, Moxifloxacin, Thorough QT study, Exposure-response modeling, J-Tpeak

Item Description

1347-8613
10.1016/j.jphs.2018.01.009