Ceftriaxone and Lansoprazole Cause QT Prolongation

Study Questions:

Does data mining of the Food and Drug Administration Adverse Event Reporting System (FAERS) and a large electronic health record (EHR) identify QT interval-prolonging drug-drug interactions (QT-DDIs), and can it lead to patch-clamp electrophysiology (EP) experiments to confirm the mechanism of the interaction?

Methods:

The authors mined 1.8 million adverse event reports for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in the EHR, the authors refuted or corroborated the putative interactions. Patch-clamp EP experiments were carried out to evaluate the top candidate drug.

Results:

In the adverse event reports, the authors found that the combination of ceftriaxone (Rocephin), a cephalosporin antibiotic, and lansoprazole (Prevacid), a proton-pump inhibitor, prolongs the QT interval. In the EHR, patients on 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, the authors confirmed that these drugs block the hERG channel in combination at clinically relevant concentrations. As a negative control, they evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports, and found no significant effect of this pair in either the EHR or in the EP experiments. Class effect analyses suggested that this interaction is 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 an increased risk of acquired long QT syndrome.

Perspective:

The FDA uses strict guidelines to evaluate the risk of acquired LQTS for new compounds, and any new non-antiarrhythmic medication associated with significant QT prolongation is not likely to gain approval. QT-DDIs are not routinely evaluated, and it may be several years before such an interaction is identified, leading to a label change. The authors show that the data mining of the FAERS and a large EHR can identify DDIs leading to QT prolongation, and that a basic EP experiment can provide further evidence of the interaction. The combination of the less specific and inherently biased retrospective analysis with patch clamp experiments can provide rapid and definitive information about the putative interactions.

Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Prevention, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD & Pediatrics and Arrhythmias, Novel Agents

Keywords: Arrhythmias, Cardiac, Ceftriaxone, Cephalosporins, Data Mining, Drug Interactions, Electrocardiography, Electronic Health Records, Electrophysiology, Lansoprazole, Long QT Syndrome, Pharmaceutical Preparations, Primary Prevention, Proton Pump Inhibitors


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