Figure 8.

Concentration-related effects of methadone on the QT interval (left panels). (A) Quantile plot showing the median and 90% CI for the linear concentration–QT_cF relationship with study-specific intercepts. (B) Quantile plot showing the median and 90% CIs for the linear concentration–ΔQT_cF relationship. Observed data from the Martell and DDI trials (squares) and Eap trial (circles) were grouped into eight quantiles and plotted as mean values± 90% CI. The shaded area encompasses the methadone concentration range observed from the pooled clinical trials. In addition, results of outlier analysis are shown as the percentages of simulated patients exceeding different QT-related risk thresholds for each methadone dose (right panels). (C) ΔQT_cF > 60 ms (dotted line) and QT_cF >480 (solid line). (D) QT_cF >500 ms for mean population baseline values of 407 ms (dotted line) and 421 ms (solid line). QT_cF, Fridericia rate-corrected QT. CI, confidence interval; DDI, drug–drug interaction; QT_cF, Fridericia rate corrected QT. (Slightly modified with permission from Florian et al. [55])