Cracking the Case on Sudden Cardiac Death and Domperidone

by Liomar Neves, Senior Scientist

Recently, the Journal of Cardiovascular Pharmacology published an original article investigating sudden cardiac death and QT interval prolongation associated with domperidone that caught the attention of our CorDynamics team.

The Report

Domperidone is a dopamine receptor antagonist not approved by FDA for sale in the US market, but is widely used in more than 100 countries. Its purported benefits are as a gastrointestinal prokinetic agent, an anti-nausea and vomiting therapeutic and more recently it has been used to promote lactation.

However, the compound has been associated with disturbances in ventricular electrophysiology. These include increases in QT interval and cardiac rhythm disturbances.

In this recent preclinical study, the authors confirm that domperidone prolongs action potential duration and suggests that the IC₅₀ for blocking the hERG channel I_Kr may be lower than previously reported.

New Evidence

The study also involved the use of prolonged domperidone exposure times, longer cycle lengths to examine reverse-use dependence, and use of rabbit hearts that are naturally heightened for sensitivity to I_Kr antagonism.

• Evidence demonstrated domperidone to have a high affinity to I_Kr and low safety margin, thus increasing risk of drug-induced long QT syndrome and potential proarrhythmogenesis.

• Additionally, the report brings attention to the limited benefits of domperidone for gastrointestinal disturbances and highlights the risk of using a low safety margin drug for a non-threatening target such as promotion of lactation.

The authors concluded the report by urging other regulatory agencies to take the FDA’s approach and ban domperidone’s use.

FDA Warns Azithromycin May Prolong QT Interval

It’s been almost a week since our return from the 2013 Society of Toxicology meeting in San Antonio. While we try to keep up with things outside the trade show, it’s hard to do.

However, one news item caught my eye during the week. In fact, it was nearly impossible to miss as the lead or top level item on all the news channels.

The FDA warned the public that the antibiotic azithromycin could cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.

In a nutshell – QT interval prolongation.

The revised label has the most robust description yet of the drug’s ability to prolong QT interval in certain subsets of patients. Which got me thinking…

So many people have taken azithromycin over the years with great success. It works effectively for taking care of common respiratory infections. Azithromycin is literally a lifesaver in developing and yet-to-develop areas for conditions such as river blindness and community related infections where compliance can be nominal.

How could the industry have missed the QT interval prolongation in azithromycin?

The answer is actually straightforward.

First, azithromycin was approved on a wide basis in 1991. This was a number of years before stringent screening for safety pharmacology effects were in place.

Second, the adverse effects appear to limited to a small subset of patients – likely related to the vulnerable substrate hypothesis for proarrhythmogenesis. But when you actually take a close look at the preclinical data – the effects of azithromycin on QT interval prolongation are indeed there to see.

Whether it’s an isolated heart protocol or a telemetry investigation, there are numerous reports from preclinical studies showing that the azithromycin prolongs QT interval under certain conditions. Additional investigations confirm the clinical database—the compound is thankfully associated with very little proarrhythmic activity.

Zofran, The FDA and Return of Cardiovascular Culprit: QT Interval Prolongation

I’m often asked: Why should our project team expend finite resources on cardiovascular safety studies for an oncology therapy or GI compound?

Today’s FDA removal of the highest dose form of Zofran (ondansetron) from the market is a prime example.

Case Study

The gastrointestinal drug ondansetron is a 5-HT3 (serotonin type 3) receptor antagonist indicated for use in the prevention of chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting.

This is an interesting scenario since ondansetron is often used as adjuvant therapy. For example, an oncology patient has nausea and vomiting induced by chemotherapy treatment. Their physician prescribes ondansetron to mitigate these severe GI side effects.  On top of all these issues, one certainly wishes to avoid prolongation of the QT interval. Thus, Drug 1 (cancer treatment) leads to Drug 2 (treatment for the side effects of Drug 1), which is what causes cardiac effects.

Preclinical QT Interval Prologation with Ondansetron

The literature demonstrates that preclinical models are predictive for the electrocardiographic effects of ondansetron. The FDA stated today that the 32 mg, single IV dose should be avoided due to the risk of QT interval prolongation, which can lead to Torsades de Pointes, an abnormal, potentially fatal heart rhythm. Learn more about QT Interval prolongation. 

Our team has published and worked extensively with preclinical models designed to detect the propensity for QT interval prolongation early in the discovery, preclinical and phase I stages. View data.

Serotonin is involved in many areas of human physiology. Drugs that alter the pharmacology of serotonin must be interrogated for cardiovascular effect regardless of the target for therapy.

World Rare Disease Day

The Future Looks Bright

It’s World Rare Disease Day and supporters of all ages are coming together to raise awareness. From my point of view, the next generation makes the future look bright.

Today, I find myself back at the University of Michigan Medical School talking with pharmacology graduate students. Many of these future researchers will dedicate their careers to developing the very drugs and therapies needed to help those struggling with unmet medical needs.

My seminar is entitled “World Rare Disease Day: Current Pharmacological Targets and Animal Models of Pulmonary Arterial Hypertension.”

I talk about my Michigan history and the career path that took me from grad student, to post doc, to industry researcher and ultimately entrepreneur. From the CorDynamics point of view, I discuss the extensive preclinical and discovery studies done for clients researching treatments for pulmonary arterial hypertension—an orphan disease.

Meanwhile, back in Illinois, kids at Spencer Loomis Elementary School are helping other kids in the hopes of eradicating some of these diseases in their lifetimes. For Dollar Denim Days, the students are purchasing denim ribbons as well as wearing their favorite pair of jeans in a nod to the Global Genes Project. The proceeds will go toward research on Rett Syndrome, a rare genetic disorder of the nervous system and the diagnosis given to the 3-year-old daughter of a former teacher at the school.

Inspired, CorDynamics pledged to match the funds raised by the Spencer Loomis Elementary students.

In the interest of full disclosure, the teacher was my oldest son’s kindergarten teacher and my youngest son still attends the school. Not to mention, Rett Syndrome is often associated with a dangerous heart condition that we regularly research—long QT syndrome.

Odds are, most of us are connected to one of the nearly 30 million Americans affected by a rare disease. From one generation to the next, I believe these connections will lead to solutions and cures.

The Short Story on Prolonged QT Interval

Over the course of my career, I’ve been asked the following questions many times:

1. What is QT Interval Prolongation?

2. Why does it matter?

QT Interval Prolongation is an increase in the time the heart normally takes to ‘reset’ itself electrically.

QT Interval Prolongation is a critical matter in drug development for several reasons.

• Drugs that increase QT interval can make the heart vulnerable to life-threatening arrhythmias.

• It is one of the leading causes for drug withdrawal over the last 20 years.

• Screening new compounds for QT interval prolongation early in development can save millions of dollars.

Is there more you’d like to know about QT Interval prolongation? The long story perhaps?

If so, get in touch. I’m happy to elaborate further.