Bridging the Gap Between hiPSC-CMs Cardiotoxicity Assessment and Clinical LVEF Decline Risk: A Case Study of 21 Tyrosine Kinase Inhibitors

Figures

• 

  Figure 1. Individual plots of TKIs on survival fraction of hiPSC-CMs for TKIs with no cardiotoxicity (A) and TKIs with cardiotoxicity (B).

• 

  Figure 2. Individual plots of TKIs on relative ATP level of hiPSC-CMs for TKIs with no cardiotoxicity (A) and TKIs with cardiotoxicity (B).

• 

  Figure 3. Individual plots of TKIs on contractile force of hiPSC-CMs for TKIs with no cardiotoxicity (A) and TKIs with cardiotoxicity (B).

• 

  Figure 4. Quantitative assessments based on the QSP-PK-TD model. The different subfigures represent the correction of drug concentration using different factors. Cp, plasma drug concentration. Fu, plasma protein binding. Kp, tissue–plasma partition coefficient. H, heterogeneous distribution.

• 

  Figure 5. Sensitivity analysis of the QSP-PK-TD model. The systematic parameters in QSP model were from a previous study [21]. HR, heart rate. TPR, total peripheral resistance. SV, stroke volume. LVEDV, left ventricular end-diastolic volume. LVESV, left ventricular end-systolic volume. index_SV, LVEDV correction coefficient of SV. FB_LVESV, feedback constant of LVESV on dissipation of LVEDV. kin_HR, kin_TPR, kin_LVEDV, and kin_SV are the zero-order production rate constants, while kout_HR, kout_TPR, kout_LVEDV, and kout_SV are the first-order dissipation rate constants for HR, TPR, LVEDV, and SV, respectively.

• 

  Figure 6. Qualitative assessments based on the QSP-PK-TD model. The different subfigures represent the correction of drug concentration using different factors. Cp, plasma drug concentration. Fu, plasma protein binding. Kp, tissue–plasma partition coefficient. H, heterogeneous distribution.

• 

  Figure 7. The combined effects of PK-TD parameters on AEAAC.

• 

  Figure 8. The combined effects of PK-TD parameters on AEMMP.

• 

  Figure 9. Schematic diagram of TKI-induced cardiomyocyte injury. Cin_TKI is the effective concentration of intracellular TKIs, and Cth is the threshold concentration of TKIs. Emax_inj is the maximum effect coefficient; hill_inj is the hill index. EC50inj is TKI concentration for half the maximum cell injury. MMP, is the mitochondrial membrane potential; kin_ATP and kin_MMP are the zero-order production rate constants for ATP and MMP, respectively. kout_ATP and kout_MMP are the first-order elimination rate constants for ATP and MMP, respectively. EC50MMP is the TKI concentration at which MMP production reaches half the maximum; EEC, TKI concentration at which average contractile force reaches half the maximum. Einj, EMMP, and EAAC are the effect of drug exposure on cell survival, MMP, and average contractile force.