Establishing assay sensitivity in QT studies: experience with the use of moxifloxacin in an early phase clinical pharmacology study and comparison with its effect in a thorough QT study.

OBJECTIVE: To compare the effect of moxifloxacin as a positive control in a single ascending dose (SAD) study with that in a thorough QT (TQT) study. METHODS: Moxifloxacin was used as a positive control in a SAD study and a TQT study during the evaluation of the QT liability of a new drug. The SAD study had enrolled 24 males and the TQT study 25 males. Both studies intensively monitored electrocardiograms (ECGs) and pharmacokinetic sampling. Effect of moxifloxacin on QTc interval was analysed in each study by intersection union test (IUT) and by exposure-response (ER) analysis and the results compared. Cost-effectiveness of this approach was computed. RESULTS: Analysis by IUT revealed that the maximum mean (90 % confidence interval (CI)) placebo-corrected change from baseline (ΔΔQTcF) in the SAD study and the TQT study were remarkably similar (10.7 (6.5; 14.9) ms vs. 9.09 (6.20; 11.98) ms, respectively). In both studies, assay sensitivity was established by the 90 % lower bound exceeding 5 ms. ER analysis revealed the slopes in both studies to be significantly different from zero and comparable. Bootstrap-predicted effects of moxifloxacin at geometric mean concentrations of ~3000 ng/mL were 8.19 (90 % CI 5.86; 10.7) ms in the SAD study and 7.33 (90 % CI 5.69; 9.70) ms in the TQT study. CONCLUSION: Moxifloxacin can be integrated effectively in a SAD study to establish assay sensitivity, and a TQT study may be replaced by a SAD study which has the required assay sensitivity. Further experience is warranted to verify this conclusion.

Thorough cardiac QTc interval conductance assessment of a novel oral tranexamic acid treatment for heavy menstrual bleeding.

OBJECTIVE: To assess the effect of a novel oral tranexamic acid treatment on cardiac repolarization in a randomized, double-blind, positive- and placebo-controlled, four-treatment single-dose cross-over inpatient study. METHODS: QTc interval and drug exposure relationship analyses were performed using triplicate digital electrocardiographs (ECGs) collected from 12-lead Holter monitors from healthy females (n = 48) with plasma drug concentrations and pharmacokinetics simultaneously evaluated over 24 h post-dose. Therapeutic (1.3 g) and supratherapeutic (3.9 g) tranexamic acid modified immediate-release doses, a positive-control 0.4 g moxifloxacin dose, and a placebo-control were administered at each period. RESULTS: All post-dose, time-matched, baseline-adjusted, mean QTcF (Fridericia's heart rate correction, QT/RR(1/3)) treatment-placebo differences (DeltaDeltaQTcF), were less than 5 milliseconds (ms) for the 1.3 g and 3.9 g tranexamic acid doses. Upper limits of the 95% confidence interval (CI) for all tranexamic acid-placebo DeltaDeltaQTcF doses were < 10 ms for all time points. Lower limits of the 95% CI for the positive-control (moxifloxacin-placebo) DeltaDeltaQTcF were > 5 ms at multiple time points demonstrating assay sensitivity. No correlation between tranexamic acid plasma concentrations and adjusted QTc intervals was observed. A positive linear relationship was observed for moxifloxacin (p < 0.01). CONCLUSION: Cardiac repolarization is not influenced by tranexamic acid at the doses studied.

Contrasting time- and rate-based approaches for the assessment of drug-induced QT changes.

The authors aim to highlight the pitfalls of different validated methods used for the assessment of drugs' effect on QT duration. Digital 12-lead Holter electrocardiograms were recorded at baseline and after a single dose of sotalol in 39 healthy subjects (age = 27.4 +/- 8.0 years). Using both time- and rate-based approaches, the authors obtained averaged QRS-T complexes every minute ("time bins") and at different RR intervals ("rate bins"). Time bins were corrected for heart rate using a subject-specific approach. The individual alpha coefficients increased from placebo (0.309 +/- 0.052) to sotalol (0.454 +/- 0.136), P < .0001. When the placebo individual alpha coefficients were applied to correct the QT interval on sotalol, the changes were >5 ms smaller than those obtained using the ON drug alpha coefficients. The "rate"-averaging process leads to a complete loss of the time course of drug effect. In conclusion, the individual correction formula calculated from the placebo condition cannot always be used for QT correction on the drug.

Quantitative assessment of ST segment elevation in Brugada patients.

BACKGROUND: ST segment elevation in the right precordial leads constitutes the electrocardiogram (ECG) hallmark of Brugada syndrome (BS). This pattern is variable and can be concealed, but the magnitude and the cause of ST segment fluctuations have been poorly investigated. OBJECTIVE: Our goal was to quantify ST changes and to assess rate and autonomic influences on ST level. METHODS: A 12-lead ECG was continuously recorded during 24 hours in 20 patients with BS (ages 49 +/- 12) and 10 healthy subjects (ages 32 +/- 7). Using two-dimensional binning we obtained average QRS-T complexes every 30 minutes (time bins) and at different RR intervals (rate bins) for each subject. ST level was measured at five different points located 90, 100, 110, 120, and 140 ms after Q onset (Qo). In BS patients, the highest ST elevation was measured 110 ms after Qo (Qo+110). RESULTS: ST level changes between time points were significantly greater in patients with BS compared with control subjects: on lead V2, the range of ST level at Qo+110 was 264 +/- 85 microV in BS and 91 +/- 22 microV in control subjects (P <.01). In BS, ST level decreased with heart rate acceleration: the difference in ST level at Qo+110 for RR = 900 and 600 ms was 55 +/- 53 microV (P <.01). HFnu was positively, although weakly, correlated with ST level (R(2) = 0.02, P <.01). CONCLUSIONS: ECG changes observed in patients with BS are related in part to heart rate influences on ST segment level. These spontaneous fluctuations over a 24-hour time period suggest that Holter recordings may improve the ECG diagnosis sensitivity in BS.

Clinical assessment of drug-induced QT prolongation in association with heart rate changes.

BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.

Individual QT-R-R relationship: average stability over time does not rule out an individual residual variability: implication for the assessment of drug effect on the QT interval.

BACKGROUND: Universal QT correction formulae have been shown to under or overcorrect the QT interval duration. Individual QT-R-R modeling has been proposed as a preferable solution for heart rate correction of QT intervals. However, the QT-R-R relationship stability over time needs to be evaluated. METHODS: The present report is part of randomized, double-dummy, and placebo-controlled 4-way crossover phase 1 study (48 healthy volunteers). Each randomized period included a run-in placebo day followed the day after by drug administration, with moxifloxacin as a positive control for QT interval measurement. Digital Holter ECG data were analyzed using the "bin" approach. For each period, individual QT-R-R relationship were calculated using two different models (linear and parabolic log-log models). RESULTS: The mean intrasubject variability for the alpha coefficient of the linear modeling (SDintra = 0.011 +/- 0.005) reached 28.6 +/- 10.2%. When the parabolic model was considered, the SDintra was 0.026 +/- 0.009 for the alpha coefficient. The QT-R-R relationship variability was in part related to long-term RR changes (R2 = 30%, P < 0.05). However, no significant time effect (ANOVA) was evidenced for QT-R-R coefficients. Moxifloxacin significantly increased the alpha coefficient of the QT-R-R relationship from 0.07 +/- 0.018 to 0.085 +/- 0.019, P < 0.05 (linear model). CONCLUSIONS: The individual QT-R-R relationship shows a residual variability in part related to long-term autonomic changes. In addition, the QT-R-R relationship might be modulated by the drug tested. As a consequence, pretherapy QT-R-R relationship obtained in a given patient cannot be used as a fingerprint throughout a drug trial.