Characterizing QT interval prolongation in early clinical development: a case study with methadone

Figures

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  Figure 1. Methadone pharmacokinetics in dogs and human subjects. Concentration versus time profiles are shown in dogs (left) and in humans (right). Lines depict predicted profiles, whereas symbols indicate observed data. The experimental protocol in dogs included methadone doses of 0.2 (green), 0.6 (red), and 2 mg/kg (dark blue). Human data were simulated to mimic a cohort of 27 subjects with 7 arms, including doses of 5 (green), 10 (red), 25 (blue), 50 (pink), 100 (brown), 250 (purple), and 500 mg (orange), with IIV variability in drug disposition parameters. Note that due to species differences in pharmacokinetics, methadone exposure after administration of a 500 mg dose yields plasma levels approximately 10‐fold higher than the concentrations observed in a typical safety pharmacology protocol in dogs.

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  Figure 2. Predicted QT profiles after administration of different doses of methadone to dogs (left) and humans (right). In humans, drug‐induced effects are based on the extrapolation of the slope parameter observed in dogs. Observations are indicated by symbols and population predictions by lines. Time is the time after dose in hours. In dogs ○ (gray) and _____ are predose values; ▵ (red) and _ _ _ _ represent 0.2 mg/kg; + (blue) and ‐ ‐ ‐ ‐ 0.6 mg/kg, ♢ (light blue) and __ __ __ 2 mg/kg methadone. In humans, different colours are used to depict each dose level, namely 5 (green), 10 (red), 25 (blue), 50 (pink), 100 (brown), 250 (purple), and 500 mg (orange) methadone.

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  Figure 3. Predicted probability of QT interval prolongation of ≥ 10 msec (upper panels) and ≥5 msec (lower panels) in humans based on a typical FTIH study design. Scenarios include the average (first and third row) and worst case scenario (second and fourth row) for the slope parameter values derived by the extrapolation from dogs. Given the gender differences in QT interval, predictions are stratified by gender: males are shown in the right panels, whereas females are depicted in the left panels. Blue line indicates the mean probability estimate; redlines: 90% credible intervals. The dashed lines indicate the observed C max range at the highest dose level (500 mg) used in the simulated study. X‐axis shows concentration in nM.

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  Figure 4. Predicted probability of QT interval prolongation of ≥10 msec (upper panels) and ≥5 msec (lower panels) in humans based on a time‐matched baseline TQT study design. Scenarios include the average (first and third row) and worst case scenario (second and fourth row) for the slope parameter values derived by the extrapolation from dogs. Given the gender differences in QT interval, predictions are stratified by gender: males are shown in the right panels, whereas females are depicted in the left panels. Blue line indicates the mean probability estimate; redlines: 90% credible intervals. The dashed lines indicate the observed C max range at the highest dose level (500 mg) used in the simulated study. X‐axis shows concentration in nM.