title: Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, New York; Department of Biomedical Informatics, Columbia University, New York, New York.
authors.forename: Tal
authors.initials: T
authors.lastname: Lorberbaum
authors.affiliation: Department of Pharmacology, Columbia University, New York, New York.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Sampson
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, New York.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Chang
authors.affiliation: Department of Cardiology, Columbia University, New York, New York.
authors.forename: Vivek
authors.initials: V
authors.lastname: Iyer
authors.affiliation: Azcert, Inc., Oro Valley, Arizona.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Woosley
authors.affiliation: Department of Pharmacology, Columbia University, New York, New York.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, New York. Electronic address: nick.tatonetti@columbia.edu.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Tatonetti
mesh_terms: D000368:Aged; D002443:Ceftriaxone / Q000009:adverse effects / Q000494:pharmacology*; D002444:Cefuroxime / Q000009:adverse effects / Q000494:pharmacology*; D057225:Data Mining; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D057286:Electronic Health Records; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006801:Humans; D064747:Lansoprazole / Q000009:adverse effects / Q000494:pharmacology*; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D018408:Patch-Clamp Techniques; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D002443:Ceftriaxone; D002444:Cefuroxime
keywords: data mining; data science; drug-drug interaction; long QT syndrome