12 / 16
Coupling data mining and laboratory experiments to
discover drug interactions causing QT prolongation
Comment by Raymond L. Woosley
MD, PhD
A
s a co-author of the recent publication
by Lorberbaum et al., I acknowledge
my obvious bias in this Commentary.
However, I welcome the opportunity to discuss
the paper and its scientific approach, orthogo-
nal learning, that is so aptly described in the
accompanying editorial by Roden et al.
Having read many ECGs, cardiologists
are familiar with the concept of using the
“orthogonal” approach to learn about the
heart by examining different leads. The article
and the accompanying editorial discuss an
orthogonal approach to “learn and confirm,”
one that we should consider in this era of
“big data” and its promise of “big learning.”
We have seen examples where research that
only examined a question from one perspective
has been misleading, eg, the value of PVC
suppression in acute MI versus in post-MI
patients. Lorberbaum et al. used multiple
scientific tools and innovative research
methods to search for potential adverse
drug-drug interactions (DDIs). Through
incremental learning and confirmation, they
were able to identify evidence for a novel DDI
that would not have been discovered using
conventional means. The next step, proof of
clinical validity, will be the final test of this
research, but nevertheless, the approach has
attractive features.
The researchers began with clinical data
(adverse events and QT prolongation) and
then tested the plausibility of their findings
in a lab model (hERG). This approach may
supplement our conventional efforts to
detect DDIs, which today begin in the lab
and then move to the clinic. Drug developers
determine whether their drug of interest
is metabolised in vitro and ask if other
drugs can inhibit or induce its metabolism.
When in vitro interactions are found, the
developer is expected to conduct confirmatory
pharmacokinetic studies in normal volunteers.
This very often leaves the question of clinical
relevance unanswered. Using clinical data as
a starting point seems attractive because we
have previously seen how human biology can
surprise us with unanticipated pharmacologic
or toxic drug effects. Few, if any, would have
predicted that a proton pump inhibitor could
so dramatically augment an antibiotic’s ability
to block the cardiac hERG channel.
Patients today take so many medications
under so many different clinical conditions
that we can never expect sponsors to conduct
clinical studies to rule out or confirm every
potential interaction. Therefore, a series of
logical orthogonal experiments such as those
applied in this research could serve as the basis
for selecting interactions with high likelihood
of clinical relevance. This will allow us to
invest our clinical resources into the study
of interactions with a greater likelihood of
improving patient outcomes.
As noted in the editorial by Roden et
al, these results alone do not at this time
support a change in the use of these drugs.
However, the findings do point to the need
for awareness and a closer examination of the
safety of their concomitant use. Perhaps of
even greater importance, the data suggest that
there may be a biological connection between
the functioning of the hERG channel and
the myocardial proton pumps that deserves
exploration. The real impact of this research
may have less to do with drug-drug interactions
and more to do with cardiac physiology.
Dr Woosley is founding
President and Chairman of
the Board for CredibleMeds
Worldwide, a non-profit
organisation dedicated to
safe use of medications.
He is Emeritus Professor
of Medicine and Pharmacology at
the University of Arizona College
of Medicine in Arizona.
Coupling data mining and
laboratory experiments to
discover drug interactions
causing QT prolongation
Journal of the American
College of Cardiology
Take-home message
•
The authors used adverse event re-
ports, electronic health records (EHR),
and laboratory experiments to develop
an efficient method for detecting QT
interval-prolonging drug–drug interac-
tions (QT-DDIs). Almost 2 million adverse
event reports confirmed the effects of
ceftriaxone in combination with lanso-
prazole in prolonging the QT interval.
A total of 1.6 million electrocardiogram
results from the researchers’ institutional
EHR were evaluated and a significantly
prolonged QT interval was detected in
patients taking combined ceftriaxone
and lansoprazole. In the laboratory, the
combination of ceftriaxone and lanso-
prazole was found to block the human
ether-à-go-go–related gene channel,
and this is thought to be the main mecha-
nism of medication-related QT interval
prolongation. Neither EHR evaluation nor
laboratory testing found an interaction
when lansoprazole was taken with an
alternative cephalosporin, cefuroxime.
•
The use of data combined with labora-
tory experiments can identify QT-DDIs.
There is a significantly increased risk
of a prolonged QT interval in patients
taking ceftriaxone and lansoprazole in
combination.
Abstract
BACKGROUND
QT interval-prolonging drug-
drug interactions (QT-DDIs) may increase the
risk of life-threatening arrhythmia. Despite
guidelines for testing from regulatory agen-
cies, these interactions are usually discovered
after drugs are marketed and may go undis-
covered 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 meas-
ure 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 cephalo-
sporin 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 sig-
nificant 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 labo-
ratory experiments is an efficient method for
identifying QT-DDIs. Combination therapy
of ceftriaxone and lansoprazole is associ-
ated with increased risk of acquired long QT
syndrome.
J Am Coll Cardiol
2016 Oct 18;68:1756-1764,
Lorberbaum T, Sampson KJ, Chang JB, et al.
Comment by Sandra M Herrmann
MD
T
his study shows that the combination
of ceftriaxone and lansoprazole prolongs
QTc interval and relates this observation
to the blockade of the human Ether-à-go-go-
Related Gene (hERG) potassium channel
blockade. The pertinent aspect is that
this study points into the direction of the
arrhythmia risks associated with proton pump
inhibitors (PPIs). These drugs are widely used
in medical practice and a growing number
of cases of hypomagnesemia with chronic
use of PPIs have been described, attributed
to impaired intestinal absorption. This is
even more pronounced in patients who are
concomitantly treated with diuretics, eg, those
with systemic hypertension. Hypokalemia
is not generally caused by PPIs alone.
However, in extreme alkalosis or with an
impaired potassium recycling system, PPIs
may cause hypokalemia even unrelated to
hypomagnesemia. The hERG encodes for a
potassium channel protein known as Kv11.1,
which colocalises with the magnesium channel
TRPM6 in the distal collecting tubules, and
interference with Kv11.1 may interfere with
magnesium reabsorption. These dynamics may
thus set up the perfect storm for torsades to
develop in those on chronic PPI therapy and
especially in combination with diuretic therapy.
Practitioner needs to take these dynamics into
consideration in the care for their patients,
particularly given that diseases such as GERD,
peptic ulcer disease, and hypertension are so
common as is the prescribing pattern of these
drugs often thought to be so harmless. H2
blockers may be considered as an alternative to
PPIs as suitable, and if not, magnesium levels
should be followed and replaced. Recovery
from hypomagnesemia is relatively quick
after stopping PPIs, usually within a few days.
While not mentioned in this study directly,
these are important aspects for daily patient
management.
Dr Herrmann is Assistant Professor of
Medicine, Mayo Graduate School of
Medicine, Mayo Clinic Rochester, Minnesota.
Practitioner needs to take these dynamics into consideration in the care for their
patients, particularly given that diseases such as GERD, peptic ulcer disease, and
hypertension are so common as is the prescribing pattern of these drugs often
thought to be so harmless.
ARRHYTHMIAS/HEART RHYTHM DISORDERS
PRACTICEUPDATE CARDIOLOGY
12