The “One‐Step” approach for QT analysis increases the sensitivity of nonclinical QTc analysis

Figures

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  FIGURE 1. Importance of correction with the appropriate slope. This figure illustrates two different QT‐RR relationships as lines A or B, or treatments A or B. Upper left: Illustrates two different linear relationships. There is a gap at an RR interval of around 500 ms. The primary question posed with this panel is “do you require any data from line A to predict the data at 500 ms RR interval for line B, or vice versa?” Upper right: Illustrates the same linear relationships with some added uniform variability. Lower left: Illustrates the QTc values – corrected QT interval if all the points were corrected using the slope for treatment A (blue solid and dashed lines). The spread of the points at 500 ms RR is widest for treatment B. Correction by this method reduced the precision of the data. Lower right: Illustrates correction of the data along its own slope. In this case, the precision is comparable for both treatments. The mean QTc value is the same in both lower panels – the method did not impact accuracy. Not illustrated is the impact of treatment B changing the heart rate. This would change the proportion of points on either side of the correction line. This would impact the mean QTc…

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  FIGURE 2. An example four (IDs = 22, 28, 37, 44) study at hour = 4. This figure illustrates for four animals at the 4 h timepoints (181–240 min postdose) the 1 min mean data recorded for all four treatments. There are four regression lines for QT‐RR for each animal. The confidence intervals around these lines at RR = 500 ms are sufficient to make confident predictions of the QT value independent of rate. The reference rate of 500 ms is indicated by the red vertical solid line. The estimated marginal means method by default uses the overall mean RR interval for the data being compared. In this case, this is 514 ms and is indicated by the black dashed vertical line.

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  FIGURE 3. Comparison of the analysis models. This figure illustrates for all 48 animals the mean treatment effect on QTc relative to vehicle 1. Sufficient data for a restricted range of RR interval (490–510 ms) was available. These QT data were not corrected for RR interval and represents the effect at the reference RR without the influence of correction method assumptions (“QT @ 500”) of treatment on the QT interval. Vehicle 2 should have no consistent effect on QTc. Moxifloxacin (80 mg/kg) caused a dose‐ and concentration‐dependent prolongation of QTc compared to vehicle 1. A solid red line at 10 ms QTc effect is provided for reference along with red dashed lines at ±5 ms.

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  FIGURE 4. Power curves for four or eight based on the analysis models. This figure illustrates the power (for p = 0.05) to detect a QTc effect for the different methods and for group sizes of four or eight animals. Dotted lines at 5 (blue) and 10 ms (red) are provided for reference. The solid horizontal line represents 80% power.

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  FIGURE 5. Mean effect and mean confidence intervals based on 1000 sampled four studies, using the One‐Step model or Conventional analysis. The mean effect of treatment relative to dose A for 1000 sampled n = 4 studies, using either the Conventional or One‐Step analysis. The ribbons illustrate the mean upper and lower 95% confidence intervals for the 1000 studies. Reference lines for 10 ms (red solid line) and ±5 ms (red dashed line) are provided for reference. The mean effects are consistent with those in Figure 3. The wider confidence intervals are consistent with the number of animals and with the power curves in Figure 4.

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  FIGURE 6. Proportion of 1000 four studies where UCI exceeds 10 ms or LCI excludes 0 ms, using the conventional or One‐Step model (O‐S). The one‐step model can also be used with a fixed RR reference value (500 ms; O‐S 500) or a model‐chosen value (O‐S Model Chosen). This figure illustrates the proportion of the 1000 studies where the UCI exceeds 10 ms (left) or the LCI exceeds 0 ms (right). Reference lines for sensitivity of 90% (at 0.9) and specificity of 90% (at 0.1) are provided for reference. LCI, lower confidence interval; UCI, upper confidence interval.