Potentially raising the risk for life-threatening arrhythmias, drug-drug interactions that prolong the QT interval could be identified through data mining and laboratory experiments, according to research published in the Journal of the American College of Cardiology.
Investigators at Columbia University discovered that adverse event reports and electronic health records, along with targeted tests, were effective in confirming the challenging-to-predict interactions — pinpointing the peril of one specific combination therapy.
Nicholas P. Tatonetti
Ceftriaxone and lansoprazole, when taken together, were associated with an elevated risk for acquired long QT syndrome in the investigation.
Tatonetti and colleagues mined 1.8 million adverse event reports in search of signs indicative of prolonged QT interval. The researchers disproved or substantiated the signals based on 1.6 million ECG results from electronic health records of 382,221 patients treated at NewYork-Presbyterian/Columbia University Medical Center.
The team then conducted patch-clamp electrophysiology experiments on cells that expressed the human ether-à-go-go-related gene (hERG) channels to establish the mechanism for prolongation.
The adverse event reports demonstrated, both directly and indirectly, that the cephalosporin antibiotic and proton pump inhibitor in combination would prolong the QT interval.
The electronic health records showed the drug combination led to longer heart rate-corrected QT intervals than either drug alone in both men (n = 934; 12 ms; 95% CI, 7-15) and women (n = 1,414; 9 ms; 95% CI, 5.2-11.3), as well as a 1.4 times higher likelihood for heart rate-corrected QT intervals greater than 500 ms, which is the current threshold for clinical concern, according to the FDA.
“Big data and data science can reveal important clinical findings, but they must be coupled with laboratory experiments to verify them,” Tatonetti said.
The laboratory tests revealed that the drugs, in combination and at appropriate concentrations, blocked the hERG channel. The investigators assessed a second combination — cefuroxime and lansoprazole — with no signs of prolonged QT interval in the adverse event reports, as a control; no effect was observed in the health records or the experiments.
“Many will want to wait for human studies, but there are many alternatives that clinicians and patients could choose if they are worried,” Tatonetti said.
Laboratory testing for hundreds of other predicted interactions are already underway, he added.
“Our goal is to characterize all drug combinations for their safety and effectiveness,” he said. “Both doctors and patients will benefit from having this information available.”
Dan M. Roden
“With polypharmacy becoming the norm, the number of potentially interacting drug pairs is vast,” Roden and colleagues wrote. “Solving the methodological challenges of developing approaches to systematically leverage these data sources will be the next frontier in identifying and preventing [adverse drug reactions].” – by Allegra Tiver
For more information:
Nicholas P. Tatonetti, PhD, can be reached at the Department of Biomedical Informatics, Columbia University, 622 W. 168th St., PH20, New York, NY 10032; email: firstname.lastname@example.org.
Disclosure: Tatonetti reports support from the National Institute of General Medical Sciences. Please see the full study for a list of the other researchers’ relevant financial disclosures. The editorial authors report no relevant financial disclosures.