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

Abstract

Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration versus time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QT interval of ≥5 and ≥10 ms. Point estimates for the slope in dogs suggested low probability of ≥10 ms prolongation in humans, whereas an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals of the drug-specific parameter in dogs. Interspecies differences in drug disposition appear to explain the discrepancies between predicted and observed QT prolonging effects in humans. Extrapolation of the effects of racemic compound may not be sufficient to describe the increase in QT interval observed after administration of methadone to patients. Assessment of the contribution of enantioselective metabolism and active metabolites is critical.

Keywords: Clinical trial simulations; PKPD modeling; QT interval prolongation; methadone; translational pharmacology..

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.

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.

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.

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.