Physiologically based pharmacokinetic-quantitative systems toxicology and safety (PBPK-QSTS) modeling approach applied to predict the variability of amitriptyline pharmacokinetics and cardiac safety in populations and in individuals

Figures

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  Fig. 1. a The workflow of the study. The consecutive steps are listed in the blocks from top to bottom. The respective software was written in square brackets. b The exploitation of collected data for model optimization, PBPK model performance verification, and PBPK-QSTS modeling purposes

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  Fig. 2. The Emax model total plasma AT concentration [μM] − RR interval length [ms] curve along with the values clinically observed (dots)

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  Fig. 3. The ratio of predicted mean concentrations to observed mean concentrations of AT (red dots) and NT (blue dots). Two-fold margin is marked in pink (Color figure online)

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  Fig. 4. The ratio of predicted to observed dose metrics: AUC for time-concentration profile of AT (red dots), AUC for time-concentration profile of NT (blue dots), Cmax for AT (green dots). Two-fold margin is marked in pink (Color figure online)

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  Fig. 5. The results of PBPK-QSTS modeling in CSS in ten Tusscher and Panfilov [26] ventricular cardiomyocyte cell model (in blue) compared to clinically observed values (in red) of three clinical trials [36, 48, 49]. The results are presented as mean with standard deviation of ∆QTc (Color figure online)

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  Fig. 6. The exemplary individual results of PBPK and PBPK-QSTS modeling in case of 67-year old female intoxicated with 2500 mg of AT [34]. a The 1st column contains profiles of AT concentrations, the 2nd has NT concentrations. The 1st row has drug concentrations in venous plasma, the 2nd has drug concentrations in the heart tissue. The black and orange horizontal lines depict the measured concentration of AT, and NT, respectively, and the time interval in which the measurement was conducted. b The QT interval length simulated in CSS in ten Tusscher and Panfilov [26] ventricular cardiomyocyte cell model (results of single simulations in green, mean of simulation results in blue) compared to clinically observed value (in orange) (Color figure online)

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  Fig. 7. The results of PBPK-QSTS modeling in CSS in ten Tusscher and Panfilov [26] ventricular cardiomyocyte cell model (in blue) compared to clinically observed values (in red). The results are presented as mean with standard deviation of QT or QTcB (Color figure online)