The Effect of Moxifloxacin on QTc and Implications for the Design of Thorough QT Studies

Bloomfield, DM; Kost, JT; Ghosh, Kalyan; Hreniuk, David; Hickey, LA; Guitierrez, M.; Gottesdiener, K.; Ja, Wagner

doi:10.1038/clpt.2008.33

Cited by 143 publications

(167 citation statements)

References 25 publications

(37 reference statements)

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“…The respective values for QT c B and QT c S were 425.3 ms (SD = 20.6 ms) and 415.2 ms (SD = 17.7 ms). Moxifloxacin administration on day 1 increased QT c F by 5.6 ms (90% CI, 1.9-9.3), which was within the expected range (22,29,30). The increase in QT c B with moxifloxacin was 11.1 ms (90% CI, 5.3-16.9) and the observed prolongation of QT c S was 5.7 ms (90% CI, 2.0-9.4).…”

Section: Corrected Qt Intervalsmentioning

confidence: 52%

Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib

Bello

Mulay

Huang

et al. 2009

Clinical Cancer Research

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Purpose: To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer. Experimental Design: Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread. Results: Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QT c F) of 5.6 ms [90% confidence interval (CI), 1.9-9.3]. Sunitinib QT c F changes correlated with exposure, but not T max . Maximum mean time-matched, placebo-adjusted QT c F was 9.6 ms (90% CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90% CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QT c F >500 ms. Concomitant granisetron produced no significant QT c F prolongation. Sunitinibrelated adverse events were as previously described. Conclusions: Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer. The QT interval represents the duration of ventricular depolarization and repolarization, and is measured with an electrocardiogram (ECG) at the beginning of the QRS interval to the end of the T wave. Key factors affecting QT interval include heart rate, autonomic tone, age, gender, time of day, electrolyte disturbances, and food. Certain pharmacologic therapeutic agents also delay cardiac repolarization and prolong QT interval; these effects are exacerbated by drug-drug interactions (1). These agents therefore increase the risk of cardiac arrhythmias, including torsade de pointes, which can degenerate into ventricular fibrillation, leading to sudden death. Consequently, evaluation of potential cardiac effects, including those on the cardiac conduction system, is a consideration in designing appropriate clinical trials to assess an agent's risk to patients, assess a compound's overall safety, and provide guidance for the clinical management of any effect.According to International Conference on Harmonization E14 guidance, all drugs must undergo a formal clinical evaluation early in clinical development to assess the potential for QT/ QT c prolongation (2). Typically, a single dedicated trial (a thorough QT/QT c trial; TQT) is included in the drug development program and is conducted in healthy volunteers at doses higher than those clinically administered (e.g., "worst case scenario") to characterize dose-response. A TQT should also be randomized and blinded. The use of a placebo control, as well as a concurrent positive control group, is important to rule out non-drug effects and to establish the sensitivity of the trial to detect a known QT interval effect. However...

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Section: Corrected Qt Intervalsmentioning

confidence: 52%

Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib

Bello

Mulay

Huang

et al. 2009

Clinical Cancer Research

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“…However, some studies involving Caucasian subjects showed larger QTcF effects [15][16][17] . Therefore, further studies are required to determine ethnicity-specific effects, especially prospectively designed direct comparisons of moxifloxacininduced QT prolongation in Asians versus Caucasians.…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Liu

et al. 2015

Acta Pharmacol Sin

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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.

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“…However, this dedicated QTc study incorporated many of the key guidance directives, including the following: (a) characterization of the response relationship using exposures higher than those achieved at the therapeutic dose, that is, the use of a supratherapeutic dose; (b) using replicate ECGs to reduce variability; (c) using a centralized core laboratory blinded to time and treatment to reduce bias and variability; (d) utilization of placebo control; (e) utilization of a crossover design with each patient serving as his/her own control; and (f) drug concentration measurements collected at the time of ECG assessment to aid in concentration-response relationships. This study was done in patients with advanced cancer, the targeted therapeutic population, and use of a positive control such as moxifloxacin that prolongs the mean QTc interval (17) was not acceptable due to the overall poor health status of the study population. Patients with advanced cancer may harbor disease or therapy-related cardiac, renal, and metabolic abnormalities, which may pose a greater risk for QT prolongation.…”

Section: Discussionmentioning

confidence: 99%

“…The study lacked a positive control that limits assessment of assay sensitivity; however, past clinical experience with similar monitoring techniques have consistently shown positive findings of QTc prolongation with positive controls (such as moxifloxacin), suggesting that this may not be a major deficiency (15,(17)(18)(19)(20)(21). Additionally, blood draws during placebo administration were not done, which may have led to potential unblinding of study therapy to patients.…”

Section: Discussionmentioning

confidence: 99%

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Münster

Rubin

Belle

et al. 2009

Clinical Cancer Research

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Purpose: This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. Experimental Design: A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C max of vorinostat. Results: Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC 0-∞ and C max values attained were on the order of ∼1.93-and ∼1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. Conclusions: Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation. (Clin Cancer Res 2009;15(22):7077-84)

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The Effect of Moxifloxacin on QTc and Implications for the Design of Thorough QT Studies

Cited by 143 publications

References 25 publications

Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib

Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib

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

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

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