Moxifloxacin‐induced QT_c interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study

Abstract

AIMWe investigated whether moxifloxacin-induced QT c prolongations in Japanese and Caucasian healthy male volunteers were significantly different. METHODSA two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QT c interval from baseline (ΔΔQT c 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 c F for each population, and the difference between the two, were calculated at a geometric mean C max 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 c F was contained within À5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. RESULTSThere were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin C max (3.27 ± 0.6 vs. 2.98 ± 0.7 μg ml -1 ), ΔΔQT c F (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at C max of 3.07 μg ml ) and concentration-response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per μg ml -1

Evaluating cardiac risk: exposure response analysis in early clinical drug development

“…In another investigation, moxifloxacin-induced QTc prolongation was compared between Caucasian and Japanese healthy subjects, using ER analysis with a single dose of 400 mg and comprising 40 subjects in each group. 34 All the aforementioned ER analyses with moxifloxacin have however used substantial sample sizes that are not representative of the number of subjects typically enrolled in an SAD study. Panicker et al 20 examined data from a TQT study in order to build 1000 datasets with 8:8 moxifloxacin:placebo subjects in a parallel design by resampling with replacement for each group.…”

Observations on conducting whole‐cell patch clamping of the hERG cardiac K+ channel in pure human serum

“…These plasma levels correspond to approximately 5–15% inhibition of hERG by cisapride in pure serum and are in the range of the calculated IC 10 value which measured 182 nM. For moxifloxacin, the total plasma levels of 20–24 μM prolonged QTc by 30–31 ms (Johannesen et al ., ) whereas two other studies showed a 2.0–2.5 ms increase in QTc for every 1000 ng ml −1 (2.5 μM) moxifloxacin yielding calculated QTc increases of 8–10 and 24–30 ms for the total plasma levels of 10 and 30 μM, respectively (Chen et al ., ; Morganroth et al ., ). These concentrations (10–30 μM) produce 3.5–9.4% inhibition of hERG channel current by moxifloxacin in serum and are close to the IC 10 value of 32 μM.…”

Vigabatrin Lacks Proarrhythmic Potential: Results from a Thorough QT/QTc Study in Healthy Volunteers

“…16,17 The AUC and C max values with a single oral dose of moxifloxacin observed in this study were similar to previously reported values. [18][19][20][21] Furthermore, as steady-state concentrations of vigabatrin are reached on the second day of multiple dosing and with minimal drug accumulation, 22 the results from this single-dose TQT are applicable to repeated clinical vigabatrin dosing. While elimination half-life is often used to predict the time to steady-state concentration, it has its limitations in predicting the duration of pharmacologic action following single dosing.…”