Clinical Trial in a Dish: Personalized Stem Cell-Derived Cardiomyocyte Assay Compared With Clinical Trial Results for Two QT-Prolonging Drugs

Abstract

Induced pluripotent stem cells (iPSCs) have shown promise in investigating donor-specific phenotypes and pathologies. The iPSC-derived cardiomyocytes (iPSC-CMs) could potentially be utilized in personalized cardiotoxicity studies, assessing individual proarrhythmic risk. However, it is unclear how closely iPSC-CMs derived from healthy subjects can recapitulate a range of responses to drugs. It is well known that QT-prolonging drugs induce subject-specific clinical response and that all healthy subjects do not necessarily develop arrhythmias or exhibit similar amounts of QT prolongation. We previously reported this variability in a study of four human ether-a-go-go-related gene (hERG) potassium channel-blocking drugs in which each subject underwent intensive pharmacokinetic and pharmacodynamic sampling such that subjects had 15 time-matched plasma drug concentration and electrocardiogram measurements throughout 24 hours after dosing in a phase I clinical research unit. In this study, iPSC-CMs were generated from those subjects. Their drug-concentration-dependent QT prolongation response from the clinic was compared with in vitro drug-concentration-dependent action potential duration (APD) prolongation response to the same two hERG-blocking drugs, dofetilide and moxifloxacin. Comparative results showed no significant correlation between the subject-specific APD response slopes and clinical QT response slopes to either moxifloxacin (P = 0.75) or dofetilide (P = 0.69). Similarly, no significant correlation was found between baseline QT and baseline APD measurements (P = 0.93). This result advances our current understanding of subject-specific iPSC-CMs and facilitates discussion into factors obscuring correlation and considerations for future studies of subject-specific phenotypes in iPSC-CMs.

Figure 1

Sample raw action potential duration recordings. Representative 20‐second action potential recordings from a healthy subject's induced pluripotent stem cell cardiomyocytes (a, g) at the baseline and after addition of (b–f) 10, 21, 70, 140, and 200 μM moxifloxacin and (h–l) 0.5, 1, 2, 4, and 8 nM dofetilide. Each subfigure represents the action potential traces from a unique well, collected at a parallel timepoint, ~30 minutes after drug administration.

Figure 2

Individual induced pluripotent stem cell cardiomyocytes (iPSC‐CMs) drug response—moxifloxacin. The baseline action potential duration (ΔΔAPD90c) response to the concentration range of moxifloxacin for all lines of subject‐specific iPSC‐CMs (subjects A through P). A linear model, represented by the dashed line, was generated to describe the ΔΔAPD90c response to moxifloxacin across the whole concentration range. The 95% confidence intervals for the model are shaded in gray.

Figure 3

Individual induced pluripotent stem cell cardiomyocytes (iPSC‐CMs) drug response—dofetilide. The action potential duration (ΔΔAPD90c) response to the concentration range of dofetilide for all lines of subject‐specific iPSC‐CMs. A linear model, represented by the dashed line, was generated to describe the APD response to dofetilide from 0.5 to 4 nM. The 95% confidence intervals for the model are shaded.

Figure 4

Baseline correlation plot. Average rate‐corrected QT (QTc) interval at baseline, as calculated as the average of 18 measurements collected over 6 days of dosing, plotted against action potential duration (APD90c) at baseline, calculated as the plate‐wide baseline averages for each line of subject‐specific cells. Error bars on both axes represent an SD above and below the mean.

Figure 5

Correlation between induced pluripotent stem cell cardiomyocyte (iPSC‐CM) and clinical drug response. (a) Action potential duration (ΔΔAPD90c) response slope vs. clinical ΔΔQTc response slope for each subject as determined via linear models of both baseline QTc (ΔΔQTc) vs. moxifloxacin concentration and ΔΔAPD90c vs. moxifloxacin concentration. (b) ΔΔAPD90c response slope vs. ΔΔQTc response slope for each subject vs. dofetilide concentration. (c) ΔΔAPD90cF moxifloxacin response slope vs. ΔΔQTc moxifloxacin response slope for each subject. (d) ΔΔAPD90c dofetilide response slope vs. ΔΔQTc dofetilide response slope for each subject. (e) The ΔΔAPD90c moxifloxacin response slopes vs. ΔΔAPD90c dofetilide response slopes, comparing the clinical responses to each drug for each subject. (f) The ΔΔQTc moxifloxacin response slopes vs. ΔΔQTc dofetilide response slopes, comparing the iPSC‐CM responses to each drug for each subject.

Figure 6

LQTS example traces with arrhythmias. Representative 20‐second action potential recordings of induced pluripotent stem cell cardiomyocytes (iPSC‐CMs) derived from a patient with long QT syndrome. (a, c, e) Show wells beating spontaneously at baseline. (b, d, f) Show those same wells with arrhythmic beating events after dosing with 4 nM dofetilide, 140 μM moxifloxacin, and 200 μM moxifloxacin, respectively.