Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes

Abstract

SummaryTo predict drug-induced serious adverse events (SAE) in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs) of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs) as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66) in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

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

“…This detailed assessment of pharmacokinetics and pharmacodynamics went beyond prior similar studies; however, no correlation was observed between baseline QT measurements and baseline APD measurements or between clinical QTc prolongation and in vitro APD prolongation to dofetilide or moxifloxacin. Our findings are in contrast to recent publications . The lack of observed correlation between in vitro and in vivo subject‐specific response to the studied drugs may be related to several factors worthy of further discussion.…”

“…There have been several studies similar to our observations on congenital LQTS iPSC‐CMs showing a relationship between donor physiology and iPSC‐CM phenotype for pathological cells possessing disease‐specific phenotypes . However, these studies can largely fall into one of two categories: those investigating specific toxicities and those studying personalized responses in a healthy cohort . One study positively identified correlation for a group of 20 subjects, made up of the most extreme responders within a much wider cohort of more than 80 subjects.…”

“…It is possible that by studying the extremes of the healthy population, as opposed to random subjects, some of the complications described above can be overcome so that QT can be correlated with iPSC‐CM's APD. Another study found a positive correlation between the slope of QT vs. moxifloxacin response in the clinic and the slope of field potential duration response in the iPSC‐CMs among a cohort of 10 randomly selected healthy subjects . This study, however, only identified a positive correlation in a subset of each subject's data.…”

“Thorough QT/QTc in a Dish”: Can Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes Predict Thorough QT Outcomes?

“…One of the QTc prolongers (moxifloxacin; false negative) and one of drugs with no QTc effect (lamotrigine; false positive) failed accurate prediction, but the reasons for this are unclear and highlight the need for additional studies. It is interesting to note that a recent study of moxifloxacin in a panel of 10 human iPSC-CM lines demonstrated consistent prolongation of the field potential (an indicator of delayed repolarization) that correlated well with QTc interval prolongation in the clinic, 7 which suggests that different iPSC-CM cell lines, test concentrations, or the end point influence the ability to detect drug-induced repolarization changes. Another complication of the Blanchette et al 1 analysis was the inclusion of mifepristone as a negative (no QTc) control, given conflicting clinical evidence.…”

Modelling of Genetic Cardiac Diseases

“…For example, Brugada syndrome (BrS) has a penetration range from 12.5 to 50%; mean penetrance of LQTS is ~40%, while overall penetrance of catecholaminergic polymorphic ventricular tachycardia (CPVT) is 78% [7]. Another convoluting factor that hinders the genotype-phenotype correlation is variable expressivity within one phenotype because some mutation carriers display all the phenotypic symptoms, whereas some only display part of mutation-specific phenotypes [8]. The clinical heterogeneity of genetic cardiac diseases suggests that ultimate disease severity (i.e., penetrance and expressivity) does not solely depend on one particular gene causing cardiac disease, but instead results from the combination of many modifying factors such as age, gender, and environmental and lifestyle factors, which either exacerbate or protect against disease [9].…”