Update on the Cardiac Safety of Moxifloxacin [25] because, although the risk of developing arrhythmias is related to the length of the QTc interval, there is a high degree of QTc interval variability [47]. In addition, many independent variables (e.g. female sex, age 65 years, bradycardia, hypokalemia, hypocalcemia, hypomagnesemia, history of cardiac disease, and concomitant QTc-prolonging medication [48-51]) markedly affect the propensity to the development of cardiac events such as TdP [52]. It is important, therefore, to assess both the ECG changes and the impact of drug-induced QTc prolongation on clinically relevant safety end points. In general, drug-induced ventricular arrhythmias have been associated with excessive QTc interval prolongation (i.e. 500 ms) [14]. The clinical significance of non-cardiac medications that induce small increases in QTc interval ( 10 ms) remains controversial. More moxifloxacin-treated patients than comparator-treated patients had post-baseline QTcB 500 ms and/or QTcB 60 ms (for example, in IV/PO studies, 22 [2.3%] vs 11 [1.1%] patients had QTcB 60 ms in the population which had ECG recorded pre-therapy and on Day 3). This difference is not unexpected since moxifloxacin is known to prolong the QTc interval in some patients. Interestingly, there was no increased risk of cardiac adverse events among these patients. Whether a correlation exists between plasma concentrations of moxifloxacin and prolongation of QTcB is still a matter of debate. Although no significant correlation was seen in a Phase III study enrolling patients with paired- valid ECGs at pre-therapy, Day 1and Day 3 [53], a linear model developed by pooling data from 20 Thorough QT (TQT) studies described the concentration-QTc relationship with a mean slope of 3.1 (2.8 – 3.3) ms per g/mL moxifloxacin [54]. This is consistent with ICH E14 analyses conducted in TQT studies where maximum effect is typically within the time interval of maximum concentration [55]. In contrast, Malik et al. observed that peak moxifloxacin concentrations were poorly correlated with QTcF prolongation [19]. In this case, it is important to note that variability in observed moxifloxacin concentrations at Cmax is less than the variability in QT prolongation and that a linear- QTc prolongation relationship was identified for moxifloxacin. Tsikouris et al, also observed a very small change between the QTc at baseline and at 2 hours post- dose, the pharmacokinetic peak concentration of moxifloxacin [56]; however, it was not manifested in clinical symptoms. A black-box warning statement was introduced on the moxifloxacin label warning that the duration of intravenous infusion should not be shorter than 60 minutes and the daily IV and PO recommended dose should not exceed 400 mg. Most reports indicating that moxifloxacin may be related to cardiac AEs such as TdP are single case reports and very often the individual had multiple risk factors for cardiac arrhythmias [57, 58]. This type of case-by-case reporting serves to highlight potential cardiac risks, but cannot be used to assess the true risk of uncommon or rare cardiac events within a large patient population. One way to do this is for all clinicians to monitor and report adverse drug events to the regulatory authorities. However, to allow the authorities to obtain a true picture of the level of risk, it is important that AE reporting is standardized to include all relevant patient Current Drug Safety, 2012, Vol. 7, No. 2 161 information, including all likely independent risk factors [52]. The benefit of using pooled randomized active-controlled clinical trial data for this type of safety study is that risk data from large numbers of patients treated with moxifloxacin can be compared with that from appropriate control subjects and comparator antimicrobials. This allows the incidence of relatively rare effects to be determined and the repeatability of relatively small changes to be analyzed. Furthermore, the data benefit from being from randomized studies and therefore patients in the two treatment groups should be balanced with respect to known, and also unknown, factors that could be associated with the outcome variables, thus making comparisons between treatment groups as fair as possible [59]. However, there are limitations to using pooled clinical trial data. Firstly, the trials included highly selected patient populations. For example, many of the studies included in this analysis excluded patients with bradycardia, electrolyte disturbances or known elevated QTc at screening or those taking concomitant anti-arrhythmic medications. This means that the patient population may not be directly representative of a typical group of patients seen in the clinic. In addition, assessment of QTc was only carried out in some of the trials included in this analysis, so data are only available for this subset of patients. As data pooling was not part of the original intention, the thresholds for reporting QTc prolongation may have been slightly different between protocols and individual investigators. A further limitation is that although this pooled analysis includes a very large patient population, it may not be large enough to identify very rare events. To uncover very rare events will require ongoing assessment of data from spontaneous reports and observational studies. Finally, these data are subject to variation because they are based on single ECG observations in individual patients not on ECG profiles (ECG may not have been measured exactly at Cmax). Despite these potential limitations, this study is the first analysis using a Phase II to IV clinical trial database to focus on the cardiac safety of moxifloxacin. The findings from our study are similar to those of a large post-marketing surveillance study with PO moxifloxacin in patients with ABS, AECB, and mild-to-moderate CAP [35]. This included 27,756 patients in a “real world” setting and showed that moxifloxacin was safe and well tolerated, with no evidence of an excess of treatment-associated cardiac events. One more recent post-marketing surveillance report on specific fluoroquinolones (moxifloxacin, levofloxacin and ciprofloxacin) reported a very low incidence of TdP in relation to the overall number of spontaneous adverse event reports (990,000) for these fluoroquinolones in the USA (total number of TdP with all FQs: n=127 [0.013%]; with levofloxacin= 55 [<0.01%], with moxifloxacin= 37 [<0.01%], and with ciprofloxacin=35 [<0.01%]) [15]. In conclusion, this analysis based on a large number of patients from randomized active-controlled Bayer-sponsored Phase II to IV moxifloxacin clinical trials confirms the favorable cardiac safety profile of moxifloxacin versus a range of currently available antimicrobial agents. The established small QTc interval prolongation that occurs with moxifloxacin did not translate into a higher risk of developing clinical cardiac AEs. Therefore, although