Female Patients Patients 65 years old Moxifloxacin QTcB Change (ms) Mean ± SD Comparatorsb QTcB Change (ms) Mean ± SD 1.8 ± 28.3 12.4 ± 21.9 7.6 ± 24.4 10.8 ± 22.4 6.7 ± 26.1 8.2 ± 24.4 6.0 ± 22.0 6.8 ± 18.0 6.9 ± 22.3 N 115 170 170 227 281 45 45 118 49 Haverkamp et al. 0.8 ± 25.5 –2.6 ± 22.0 –4.0 ± 27.4 –2.5 ±21.4 –3.2 ± 29.0 1.1 ± 22.4 1.5 ± 21.8 2.8 ± 17.4 1.6 ± 21.1 160 Current Drug Safety, 2012, Vol. 7, No. 2 Table 8. QTcB Changes in Patient Subgroups at Higher Risk of Cardiac Events Indication Patient Groupa Time QTc Measured Post-Dose PO studies Post-baseline IV/PO studies in CAP IV/PO studies in cSSSI A A B C A A B C Day 1 Day 3 Day 1 Day 3 Day 1 Day 3 Day 1 Day 3 N 434 158 158 205 239 54 54 184 62 Moxifloxacin QTcB Change (ms) Mean ± SD 7.2 ± 25.3 12.7 ± 22.3 7.8 ± 24.3 12.4 ± 21.8 6.7 ± 27.2 7.4 ± 19.8 7.3 ± 18.7 10.4 ± 16.5 6.2 ± 21.0 N 416 181 181 226 260 58 58 164 60 Comparatorsb QTcB Change (ms) Mean ± SD 0.8 ± 24.1 0.7 ± 20.3 –2.1 ± 26.5 0.4 ± 20.2 –3.4 ± 27.2 –1.3 ± 17.4 –8.7 ± 22.0 1.5 ± 14.8 –8.4 ± 21.8 N 136 179 179 248 286 33 33 111 37 SD = standard deviation; PO = oral administration; IV/PO = sequential intravenous/oral administration; CAP = community-acquired pneumonia; cSSSI = complicated skin and skin structure infections; = not applicable. aGroup A = patients with ECG measurements at baseline, Day 1 and Day 3; Group B = patients with ECG measurements at baseline and Day 1; Group C = patients with ECG measurements at baseline and Day 3. bFor a list of comparators see Table 1. Much of the cause for discrepancy in correction factors is because no single mathematical transformation can describe the rapidly changing nonlinear dynamics of the QT-RR interval relationship. The relatively large differences observed at Day 3 post-baseline between the findings derived from the two correction formulas (QTcB and QTcF) in the IV/PO CAP and cSSSI studies for both moxifloxacin and comparator-treated patients are most likely related to the differences in heart rate at the different time points in these populations. Both the Bazett’s and Fridericia’s formulas over-correct at high heart rates with the effect being more pronounced with the Bazett’s formula [4, 40]. In patients where the heart rate decreases between time points (i.e. during the course of therapy), the overcorrection decreases in numerical terms with the Bazett’s formula compared to the Fridericia’s formula, and the absolute increase in QTc appears to be larger using the Fridericia’s formula than when using the Bazett’s formula. In comparator-treated patients, changes in QTcB from baseline were generally small and positive at Day 1 post-baseline, and small and negative (a shortening of the QTc interval) at Day 3 post-baseline. Post- baseline changes in comparator-treated patients were always positive (1–3 ms) when using the Fridericia’s formula. In subgroups generally thought to be more susceptible to abnormal QTc prolongation (women and those 65 years old), the QTcB prolongation with moxifloxacin was generally small and consistent with that seen in the overall population. In this analysis, where ECG data were available, only small increases in QTc were observed. This did not translate into clinical cardiac events. That prolongation occurring at relatively low levels may be due to the lack of effect of moxifloxacin on ion channels other than IKr/hERG such as IKr/KvLQT1/min K channel, which is unaffected by moxifloxacin even at high concentrations [41]. The 4–10 ms prolongation in QTcB (and 6–14 ms in QTcF) observed with moxifloxacin falls well below the likely threshold value (approximately 60 ms) for eliciting a cardiac AE that may be a surrogate clinical marker of TdP [35, 42]. Similarly, a review of data from animal models indicates an absence of TdP when moxifloxacin was administered at clinically relevant dosages and confirms the low rate of cardiac AEs seen in the current analysis [43]. The predictable pharmacokinetic properties of the drug [16] and its lack of interaction with cytochrome P450 [44] may also contribute to the lack of cardiac events seen. The results of the current study support those from extensive testing in preclinical studies, which showed that the QTc prolongation observed with moxifloxacin is generally small and highly reproducible [37-39], and independent of the sex, age, or race of the subject [19]. The small QTc interval-prolonging effect of moxifloxacin is now acknowledged by the regulatory agencies, and is implicitly recognized by the EMA, the US FDA, and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use as a positive control in thorough QTc studies used to assess the QTc effect of new compounds in Phase I trials [42, 45]. Although this analysis lacks data from placebo-controlled clinical trials; the reproducibility and the degree of QTc prolongation induced by moxifloxacin makes the drug useful as a positive control in investigating the pro-arrhythmic potential of new non-cardiac drugs. Fluoroquinolones have different potency of inhibiting the Ikr/hERG potassium channel and as expected, prolongation of the QT interval consequently matches their IC50 value when they are administered at their recommended doses. The potential for QTc prolongation associated with moxifloxacin may be higher than that for the other fluoroquinolones currently on the market. However recent reviews of available preclinical and clinical studies concluded that the overall risk of TdP associated with these agents including moxifloxacin is small [30, 46]. Simply observing a prolongation of QTc interval does not necessarily predict the risk of ventricular arrhythmias