Author + information
- Received October 6, 2015
- Revision received July 11, 2016
- Accepted July 12, 2016
- Published online October 18, 2016.
- Tal Lorberbaum, MAa,b,
- Kevin J. Sampson, PhDc,
- Jeremy B. Chang, PhDb,
- Vivek Iyer, MD, MSEd,
- Raymond L. Woosley, MD, PhDe,
- Robert S. Kass, PhDc and
- Nicholas P. Tatonetti, PhDb,∗ ()
- aDepartment of Physiology and Cellular Biophysics, Columbia University, New York, New York
- bDepartment of Biomedical Informatics, Columbia University, New York, New York
- cDepartment of Pharmacology, Columbia University, New York, New York
- dDepartment of Cardiology, Columbia University, New York, New York
- eAzcert, Inc., Oro Valley, Arizona
- ↵∗Reprint requests and correspondence:
Dr. Nicholas P. Tatonetti, Department of Biomedical Informatics, Columbia University, 622 West 168th St., PH20, New York, New York 10032.
Background QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years.
Objectives Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs.
Methods 1.8 million adverse event reports were mined for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in our institutional EHR, these putative interactions were either refuted or corroborated. In the laboratory, we used patch-clamp electrophysiology to measure the human ether-à-go-go-related gene (hERG) channel block (the primary mechanism by which drugs prolong the QT interval) to evaluate our top candidate.
Results Both direct and indirect signals in the adverse event reports provided evidence that the combination of ceftriaxone (a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor) will prolong the QT interval. In the EHR, we found that patients taking both ceftriaxone and lansoprazole had significantly longer QTc intervals (up to 12 ms in white men) and were 1.4 times more likely to have a QTc interval above 500 ms. In the laboratory, we found that, in combination and at clinically relevant concentrations, these drugs blocked the hERG channel. As a negative control, we evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports. We found no significant effect of this pair in either the EHR or in the electrophysiology experiments. Class effect analyses suggested this interaction was specific to lansoprazole combined with ceftriaxone but not with other cephalosporins.
Conclusions Coupling data mining and laboratory experiments is an efficient method for identifying QT-DDIs. Combination therapy of ceftriaxone and lansoprazole is associated with increased risk of acquired long QT syndrome.
Mr. Lorberbaum is supported by National Institute of General Medical Sciences (NIGMS) training grant T32GM082797. Mr. Lorberbaum and Dr. Tatonetti are supported by NIGMS grant R01GM107145. Drs. Sampson and Kass are supported by National Institutes of Health (NIH) grant 5R01GM109762-02. Dr. Iyer is supported by NIH grant K08HL116790.
Dr. Tatonetti is a compensated advisor to Advera Health, Inc.; he declares no conflict of interest. Dr. Woolsey is an uncompensated officer of the nonprofit organization Azcert.org, which is supported by U.S. Food and Drug Administration Safe Use Initiative contract HHSF223201400189C and sponsors the CredibleMeds.org website used in this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 6, 2015.
- Revision received July 11, 2016.
- Accepted July 12, 2016.
- American College of Cardiology Foundation