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Prescription drugs
Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.
The team found they could accurately identify those TKIs already known to be the most dangerous.
The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.
“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.
“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”
Dr Wu and his colleagues described this research in Science Translational Medicine.
The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.
The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.
Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.
The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.
High cardiotoxicity
Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.
These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.
Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.
The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.
This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.
They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.
“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”
