Discovering drug interactions that cause QT prolongation

Last Updated: 2016-10-18

By Will Boggs MD

NEW YORK (Reuters Health) - Data mining and laboratory experiments have been combined to identify an interaction between ceftriaxone and lansoprazole that significantly prolongs the QT interval, researchers report.

"Data science is an effective and efficient approach for prioritizing drug-drug interaction signals," Tal Lorberbaum from Columbia University, New York City told Reuters Health by email. "Each data source used in the study has its flaws, but when we begin to see the evidence mounting over three independent datasets, it gives us confidence that this is a true signal."

Prolongations of the QT interval, an adverse effect of more than 40 medications, are associated with a significant risk of torsades de pointes, a ventricular tachycardia that can result in sudden death.

Lorberbaum and colleagues combined evidence of QT interval-prolonging drug-drug interactions (QT-DDIs) from the FDA Adverse Event Reporting System (FAERS) and the electronic health records (HER) at New York-Presbyterian/Columbia University Medical Center (CUMC-EHR) to identify a possible interaction between the proton-pump inhibitor lansoprazole and the cephalosporin antibiotic ceftriaxone.

As a negative control, they also evaluated the combination of cefuroxime and lansoprazole, which did not match the side effect profile for QT prolongation in FAERS.

Among patients taking ceftriaxone with lansoprazole, the corrected QT (QTc) interval was prolonged by 12 ms in male patients and by 9 ms in female patients, compared with taking either drug alone.

The largest effects were seen in white men (12 ms increase) and in black women (12 ms increase).

QTc was prolonged to 500 ms or more, an accepted threshold for clinical concern, in 19% of men taking the combination versus only 14% of patients taking only one of the drugs.

There was no significant change in QTc interval for patients prescribed the negative control combination.

In laboratory experiments, lansoprazole alone (but not ceftriaxone alone) caused a drop in current in the hERG potassium channel, and the addition of ceftriaxone to lansoprazole resulted in a dose-dependent drop in current, suggesting a physiological mechanism for the interaction.

"Given that we found the interaction to be specific to ceftriaxone and not other cephalosporin antibiotics, physicians can consider an alternative to ceftriaxone when patients are already taking lansoprazole," Lorberbaum said. "At this stage we are not proposing that these results take the place of a controlled prospective clinical trial, and we are in the process of setting up such a trial. However, it's prohibitive from both a time and financial standpoint to prospectively evaluate all possible drug combinations, and this study provides a way to prioritize potential interactions for validation in the lab and the clinic."

"This work forms the basis for a comprehensive pipeline linking millions of adverse event reports to thousands of patients in electronic health records to individual human cells for the purpose of identifying dangerous drug interactions and improving patient safety," he concluded.

Dr. Dan M. Roden from Vanderbilt University Medical Center, Nashville, Tennessee, who coauthored an editorial published with the paper online October 18 in the Journal of the American College of Cardiology, told Reuters Health by email, "I think this is a provocative result, but each of the findings has some weaknesses. Taken together they support each other and so make an interesting story. What is missing is a study that actually demonstrates that the combination prolongs QT in people to a greater extent than each of the individual drugs alone. I don't think the data presented here are sufficient to relabel the drugs."

"Analysis of big data sets (like from FAERS or the EHR) is an interesting and very promising source of information to advance knowledge and generate hypotheses for further testing," he said. "The more generic message which is equally or more important is that drugs should only be prescribed when the perceived benefit outweighs the perceived risk."

Dr. Barbara Wisniowska from Jagiellonian University Medical College, Krakow, Poland recently reviewed the extent of drug-drug interactions and QT prolongation in clinical trials. She told Reuters Health by email, "Modeling and simulation is not a scientific curiosity anymore; it is a well-established, widely accepted, and validated method which can help physicians and other health specialists to individualize and optimize pharmacotherapy."

"We know from the paper that patients on lansoprazole-ceftriaxone combination have increased risk of QT prolongation, but what is the resulting incidence of clinically relevant adverse events?" she wondered. "It can be still too low to introduce a general rule and avoid concomitant prescribing routinely."

SOURCE: http://bit.ly/2dXdBqD and http://bit.ly/2dUPrvA

J Am Coll Cardiol 2016.