Integrated hiPSC-based liver and heart microphysiological systems predict unsafe drug-drug interaction

Abstract

Microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS-both built with the same hiPSC line-to study drug-drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to nonarrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish functional integration of isogenic hiPSC-based liver and cardiac MPSs, which allows screening for DDI, and thus drug efficacy and toxicity, in the same genetic background.

Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics

“…Furthermore, Lee-Montiel et al [ 98 ] recently created a multi-organ system consisting of hiPSC-derived hepatocytes and cardiomyocytes to study the metabolic conversion of cisapride to non-arrhythmogenic norcisapride through cytochrome P450 enzyme. This cisapride metabolism led to arrhythmia in the cardiac model.…”

“…This cisapride metabolism led to arrhythmia in the cardiac model. The authors were able to show functional integration of these systems allowing drug–drug screening and testing for toxicity [ 98 ]. Rajan et al [ 99 ] developed an integrated system to accommodate six tissue constructs including liver, cardiac, lung, endothelium, brain and testes organoids.…”

Liver–Heart on chip models for drug safety

“…However, when co-administered with CYP3A4 inhibitors (e.g., the antifungal ketoconazole), the inactivation of cisapride is impaired, and this indeed caused its withdrawal from the market. 112 Lee-Montiel et al 113 were recently able to recapitulate this condition in a hiPSC-based MOoC system where liver and heart individual OoC were fluidically connected. In this view, MOoC models encompassing the liver tissue might have the ability to predict unforeseen medical complications due to DDIs, giving unprecedented information in the DDP, by studying and determining which DDIs effects (e.g., unexpected cardiotoxicity) are due to liver metabolism on other tissues.…”

Multiplexed microfluidic platform for stem-cell derived pancreatic islet β cells

“…Advances in culture conditions now support viability and functionality of stem cell-derived or primary tissues representative of different organs for over a week in culture within the MPS. 7–9 The MPS platform incorporates microfluidic flows to provide tissues with culture medium circulation at volumes that are computationally predictable and more physiological relevant than static well plate culture. The lower volume of culture media is more amenable for concentrating biomolecules that could be of interest for drug discovery, and large-scale testing of more expensive reagents and molecules within small volumes.…”