Moxifloxacin‐induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study. (2nd July 2015)

• Record Type: Journal Article
• Authors: Morganroth, Joel; Wang, Yaning; Thorn, Michael; Kumagai, Yuji; Harris, Stuart; Stockbridge, Norman; Kleiman, Robert; Shah, Rashmi
• Is Part Of: British journal of clinical pharmacology. Volume 80:Number 3(2015:Sep.)
• Page Start: 446
• Page End: 459
• Publication Date: 2015-07-02
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12684
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12684-sec-0001" sec-type="section"> <title>Aim</title> <p>We investigated whether moxifloxacin‐induced QT<sub>c</sub> prolongations in Japanese and Caucasian healthy male volunteers were significantly different.</p> </sec> <sec id="bcp12684-sec-0002" sec-type="section"> <title>Methods</title> <p>A two period, randomized, crossover, ICH‐E14‐compliant thorough QT (TQT) study compared placebo‐corrected changes in QT<sub>c</sub> interval from baseline (ΔΔQT<sub>c</sub>F) and concentration–effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQT<sub>c</sub>F for each population, and the difference between the two, were calculated at a geometric mean <italic>C</italic><sub>max</sub> of moxifloxacin using a linear mixed effects model. The concentration–effect slopes of the two populations were also compared. Equivalence was concluded if the two‐sided 90% confidence interval of the difference in ΔΔQT<sub>c</sub>F was contained within −5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2.</p> </sec> <sec id="bcp12684-sec-0003" sec-type="section"> <title>Results</title> <p>There were no statistically significant differences between the two populations studied, Japanese <italic>vs</italic>. Caucasians, respectively, for moxifloxacin <italic>C</italic><sub>max</sub> (3.27 ± 0.6 <italic>vs</italic>. 2.98 ± 0.7 µg ml<sup>–1</sup>), ΔΔQT<sub>c</sub>F (9.63 ± 1.15 <italic>vs</italic>. 11.46 ± 1.19 ms at <italic>C</italic><sub>max</sub> of 3.07 µg ml<sup>–1</sup>) and concentration–response slopes (2.58 ± 0.62 <italic>vs</italic>. 2.34 ± 0.64 ms per µg ml<sup>–1</sup>). The difference in the two ΔΔQT<sub>c</sub>F of −1.8 (90% CI −4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre‐specified equivalence limits.</p> </sec> <sec id="bcp12684-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Moxifloxacin‐induced QT<sub>c</sub> prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT‐prolonging drugs are needed to clarify whether inter‐ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study.</p> </sec> </abstract>