Session S93.4

T-Wave Morphology as a Covariate in Drug-Induced QTc Prolongation

JJ Struijk*, C Graff, J Matz, MP Andersen, JK Kanters,
J Nielsen, JQ Xue, E Toft

Aalborg University
Aalborg, Denmark

The antibiotic drug moxifloxacin has a favorable cardio-vascular safety profile and is recommended as a positive control in thorough QT studies, whereas the antiarrhythmic drug d, l-sotalol has a reported incidence of Torsade de Pointes between 1.8% and 6.8%. We compared the relationship between changes of T-wave morphology and QT prolongation. Since both drugs are IKr blockers, it might be expected that this relationship is similar for the two drugs. Two studies were analysed. In a first study, 62 healthy subjects received 400 mg moxifloxacin on day 7. In a second study, 21 healthy subjects received 160 mg d, l-sotalol on day 2 and 320 mg on day 3. Both studies included a full baseline day where no drug was given. 12-lead ECGs were extracted from digital Holter at eleven different time points on all days. QT intervals were measured using GE Healthcare’s 12SL algorithm and corrected for heart rate using the Fridericia formula (QTcF). A principal component median beat was calculated from independent leads I, II, V1-V6, the T-wave of which was used to determine a combined score of repolarization morphology (MCS), based on asymmetry, flatness and notching. Time-matched changes from baseline (?) were evaluated for all recordings and used to compute mean changes of QTcF and MCS. The electrocardiographic differences between the drugs at peak changes from baseline were greater for MCS than for QTcF. Peak ?MCS(moxifloxacin) was 14% of peak ?MCS(160 mg sotalol), whereas peak ?QTcF(moxifloxacin) was 27% of peak ? QTcF(160 mg sotalol). Relative to 320 mg sotalol those numbers were 7% for MCS and 16% for QTcF. There was a steeper parabolic regression line for ?MCS as function of ? QTcF for both doses of d, l-sotalol compared to moxifloxacin, p<0.001. Consequently, at identical ?QTcF, ? MCS was more pronounced for d, l-sotalol than for moxifloxacin. The changes in morphology, for any given QTcF prolongation, were significantly greater for d, l-sotalol than for moxifloxacin, which might be associated with the different risk profiles of the two drugs. We thus propose to investigate whether concurrent assessment of QTcF and MCS might be used to assess the the proarrhythmic risk of drugs.

(Abstract Control Number: 10)