Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized, single-blind, crossover study

Abstract

Aim: To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers. Methods: This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin. Results: The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects. Conclusion: Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers.

Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients

“…drugs if not well tolerated or suggested to include in case of isoniazid resistance (3)(4)(5). In general, the toxicity profile of moxifloxacin is rather mild, though it includes concentration-dependent corrected QT interval prolongation and, rarely, tendinopathy (6)(7)(8)(9). A clinically relevant drug-drug interaction is the combination of moxifloxacin with rifampin, since these two drugs can be used concomitantly in TB treatment.…”

Sensitivity and Reliability of Halothane‐anaesthetized Microminipigs to Assess Risk of Drug‐induced Long QT Syndrome

“…Similar trends in the heart rate and PR interval were observed in the halothane-anaesthetized dogs, which did not achieve statistical significance [7]. Meanwhile, the negative chronotropic and dromotropic effects have not been reported in human beings [12]. The cardiohemodynamic results indicate that moxifloxacin-induced histamine release might not occur in microminipigs, whereas these electrophysiological ones suggest that microminipigs may be more sensitive animals for detecting the negative chronotropic and dromotropic effects of moxifloxacin than dogs.…”

“…In this study, we used microminipigs to investigate the pharmacokinetic and cardiovascular profiles of moxifloxacin and terfenadine, which are known to induce ‘benign’ and ‘malignant’ QT interval prolongation, respectively . A fluoroquinolone antibiotic moxifloxacin is known to induce mild QT interval prolongation and has been recommended as a positive control by regulatory authorities to evaluate the sensitivity and reliability of QT/QTc studies because of its absence of clinical data on the onset of torsade de pointes . Meanwhile, an antihistamine, terfenadine, has been withdrawn from the market in 1997 because of its high risk of QT interval prolongation followed by the onset of torsade de pointes .…”

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.…”