Abstract
Animal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, we quantified changes in contractility, voltage, and/or Ca2+ handling in 2D monolayers or 3D engineered heart tissues (EHTs). Protocols were unified via a drug training set, allowing subsequent blinded multicenter evaluation of drugs with known positive, negative, or neutral inotropic effects. Accuracy ranged from 44% to 85% across the platform-cell configurations, indicating the need to refine test conditions. This was achieved by adopting approaches to reduce signal-to-noise ratio, reduce spontaneous beat rate to ≤ 1 Hz or enable chronic testing, improving accuracy to 85% for monolayers and 93% for EHTs. Contraction amplitude was a good predictor of negative inotropes across all the platform-cell configurations and of positive inotropes in the 3D EHTs. Although contraction- and relaxation-time provided confirmatory readouts forpositive inotropes in 3D EHTs, these parameters typically served as the primary source of predictivity in 2D. The reliance of these “secondary” parameters to inotropy in the 2D systems was not automatically intuitive and may be a quirk of hiPSC-CMs, hence require adaptations in interpreting the data from this model system. Of the platform-cell configurations, responses in EHTs aligned most closely to the free therapeutic plasma concentration. This study adds to the notion that hiPSC-CMs could add value to drug safety evaluation.
Highlights
Through blinded testing across multiple geographical sites, we evaluated the ability of 7 different platform-cell combinations to predict whether drugs of interest to the pharmaceutical industry were positive, negative, or neutral inotropes
We achieved this by examining contractility parameters (CA, CT, and RT), as well as using Ca2þ transients and/or electrophysiology to assist in decision making in some instances
After refinement involving slowing of beat rate to below 1 Hz (Figure 5, Supplementary Figure 6), CA was highly informative of positive inotropes (PIs) in the engineered heart tissues (EHTs) system but far less so in the 2D systems
Summary
Combined with ICH E14 (Food and Drug Administration, 2005a) guidelines on electrocardiogram monitoring, drug withdrawal due to electrical dysfunction has reduced, with no reported incidences since 2007 These approaches have improved safety, but the relatively poor specificity for predicting human outcomes and overconservativism of the assays has raised concern that promising drug candidates may be abandoned too early due to false positives (Gintant, 2011). Greater predictivity during the early stages of the drug development pipeline will require certain attributes from the chosen assays These include being of human origin, suitable longevity for acute and chronic studies, compatible with medium-throughput analysis, reflective of working cardiomyocyte physiology and function, and compliant with 3Rs polices. This reduces the attractiveness or relevance of many existing systems, such as those involving animal models. This is true for human- and animalderived primary cardiomyocytes, which rapidly dedifferentiate in culture, lose viability, or become overrun with fibroblasts
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