Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone

Figures

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  Fig. 1. Metabolic conversion of methadone to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP) by cytochrome P450 (CYP450)

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  Fig. 2. Typical extracellular field potential waveform consisting of a rapid upstroke corresponding to depolarization, a slow wave/plateau and a repolarization peak. Signals were generated under the baseline condition (0.1% (v/v) DMSO) in Pluricyte cardiomyocytes cultured in six-well MEA-chips measured by the MEA2100-System platform of MCS

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  Fig. 3. Schematic diagram of the PBK model of methadone including a submodel for EDDP

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  Fig. 4. Concentration–response curves for the effect of methadone (circles), EDDP (squares) and EMDP (triangles) on FPDc in hiPSC-CM detected by the MEA. The response of the baseline condition (0.1% (v/v) DMSO) was set at 100%. Data represent the mean of 4–9 wells with in total 26–38 electrodes. Each data point represents the mean ± SD. Statistically significant changes in response compared to the solvent control are marked with * with p < 0.05: *, p < 0.01: ** and p < 0.001: ***

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  Fig. 5. Concentration-dependent formation of EDDP in incubations with human liver microsomes. Data represent the mean of three independent experiments. Each data point represents the mean ± SD

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  Fig. 6. Blood concentration–time curves of methadone in human predicted with the PBK model (lines) and published in vivo data (dots) after a repeated oral dose of 70 mg/day for 60 days a (Foster et al. 2000) and 100 mg/day for 30 days b (Liu et al. 2007)

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  Fig. 7. Normalized SCs of PBK model parameters for the prediction of steady-state Cmax of methadone in the heart venous blood upon oral repeated doses of 20 mg/day (white bars) and 200 mg/day (black bars). Model parameters with normalized SC with an absolute value higher than 0.1 (dotted lines) are shown. BW body weight, VLc fraction of liver, PRmet partition coefficient rapidly perfused tissue:blood of methadone, ka absorption rate constant, Fa oral fraction absorbed, MPL liver microsomal protein yield, Vmaxc unscaled maximum rate of methadone metabolism in liver, Km Michaelis–Menten constant for methadone metabolism in liver

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  Fig. 8. Predicted dose–response curves for cardiotoxicity of methadone obtained using PBK modeling-based reverse dosimetry compared to in vivo dose–response data derived from literature. The curves represent the prediction based on a fu,p of 0.22 (black line), 0.15 (red line), 0.055 (blue line) and 0.034 (green line). Symbols represent the data obtained from case reports, case series of individuals (orange triangles) (Esses et al. 2008; Fredheim et al. 2006; Krantz et al. 2002) and other studies as follows: Bart et al. (2017) (purple circle); Carlquist et al. (2015) (orange square); Chang et al. (2012) (green circle) Chowdhury et al. (2015); (dark blue cross); Cruciani et al. (2005) (green cross) Eap et al. (2007); (green star); Ehret et al. (2006) (dark blue triangle) Fareed et al. (2013); (dark blue circle) Heesch et al. (2015); (dark blue star) Krantz et al. (2005); (orange circles) Maremmani et al. (2005); (green square); Martell et al. (2005) (green triangle) Peles et al. (2007); (orange star); Reddy et al. (2010) (orange circles) Roy et al. (2012); (dark blue square). The in vivo data are summarized in Table S1 and S2 (color figure online)

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  Fig. 9. Comparison of BMDL values derived from the predicted dose–response curves for human cardiotoxicity of methadone presented in Fig. 8 (lines) and therapeutic dose levels reported in the literature (boxes filled with horizontal lines)