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.

Validated Anesthetized Model Screens Cardiovascular Effects Early

We have been getting a lot of communication lately from clients looking to outsource larger blocks of screening cardiovascular studies.

One frequently requested model is the anesthetized guinea pig assessment. We’ve been conducting this model for nearly ten years.  So we thought it was time to refresh the original validation dataset with the expertise we’ve gained to share with clients and colleagues interested in leveraging this model.

View Validation Data

The preparation uses a well-characterized method to screen for cardiovascular effects early.

• Guinea pigs are anesthetized and instrumented for hemodynamics and electrocardiography.
• Cardiovascular parameters such as blood pressure, heart rate, and ECG are measured.
• Cardiac functional assessments can also be provided.

As such, we have conducted experiments with a number of ‘cardio-active’ compounds. Verapamil (primary effects on PR interval and blood pressure), pimobendan (heart rate), flecainide (QRS duration), and E-4031 (QT interval) were examined in the model.  We have posted the results to our website, the dataset is quite nice.

A benefit of the model is the ability to perform pharmacokinetic assessments to interrogate PK-PD relationships. The other plus is the aggressive timeline. In most cases, we can get full information on a compound to the client within 2-3 days.

Please take a look, and feel free to contact us with any questions.

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.

The Case for Cardiovascular Safety Studies

What Drug Developers Need to Know….

The FDA and the Committee for Proprietary and Medicinal Products (CPMP) firmly advocate that preclinical and clinical tests for adverse cardiovascular potential be performed for all new pharmaceutical compounds, regardless of the intended therapeutic application.

Why?

• Over the past decade, several non-cardiac drugs have been under intense scrutiny due to unanticipated reports of morbidity and mortality associated with adverse cardiac events, namely an increased incidence of life-threatening arrhythmias.

• Potential to trigger adverse cardiovascular events has become a leading cause for removal of drugs from the market.

What Should We Look For?

• Of particular interest in cardiovascular safety assessment are the electrophysiologic effects of an agent, such as its consequences on QT interval.

• In addition, the hemodynamic consequences of a compound are also important to investigate.

How Should We Investigate?

The key is to accurately, affordably and efficiently determine the cardiovascular effects of novel therapeutic compounds. It is important to screen the electrophysiologic and hemodynamic effects of test articles using a variety of applicable and validated methods.

• Langendorff Isolated Heart
• Telemetry
• Anesthetized Studies
• Ion Channels

Fulfilling this unique need and collaborating on this issue is what our team does best. We welcome your thoughts and discussions on the topic.

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.

Guinea Pigs Require Expertise; Provide Effective Model

At recent scientific conferences I’ve noticed a continued interest in using the guinea pig to screen for unanticipated cardiovascular activity of lead candidates.

At CorDynamics, we have used the guinea pig as an effective model for cardiovascular testing, when appropriate. Since they are smaller in size, guinea pigs can serve as viable species when compound supply is limited. In some cases, the guinea pig can use five times less compound to conduct studies than amounts needed for their larger non-rodent counterparts, such as rabbits.

While a plus in terms of compound conservation, their small size and inherent anatomical obstacles do pose potential roadblocks. This is especially true in the hands of less experienced technical personnel. Guinea pigs have rather obscure vascular access due to the lack of a tail and their orogastric structure can make orally dosing somewhat challenging.

Our team has worked extensively with the guinea pig to develop an expertise to overcome these inherent challenges. With this know-how at our disposal, we’ve been able to conduct isolated heart, anesthetized and conscious/telemetry guinea pig studies for a wide variety of clients. One of our latest developments is the validation of an ultra high fidelity QT interval correction in this species using a quasi beat-to-beat approach via telemetry.

Certainly, the guinea pig is not appropriate for every situation that may typically use a smaller animal such as the rat. However, with careful planning and expert execution, this species does indeed play a valuable role in the successful de-risking funnels employed by a number of our biopharmaceutical clients.

Stem Cells Studies Create More Questions than Answers

In the last year, exciting breakthroughs in cellular research have crossed the newswires with increasing regularity. The potential of novel treatment modalities, as well as insight into the genesis of numerous pathologies is quite compelling. Within nonclinical safety assessment, scientists are assessing the value of stem cell in vitro assays for predicting drug-induced toxicity.

The following data suggests against relying solely on pure in vitro assays, including stem cell based paradigms and focused ion channel studies, for early decision making and compound selection. This is especially true in the prediction of cardiovascular safety.

In 2008, our laboratories interrogated over 120 discrete compounds in the isolated perfused heart for their potential to interact with cardiac function. A majority of these studies were conducted in response to direct evidence of ion channel blockade (for example, I_Kr [hERG] antagonism) or as part of a standard testing funnel within the individual Sponsor’s safety assessment function.

Although we had extensive anecdotal experience that would ultimately validate the outcome, upon analysis of the data we are able to state that pure in vitro assays will not accurately predict the full integrative cardiac effects of many late discovery compounds or preclinical development candidates. In fact, these assays often introduce uncertainty into the testing funnel due to their lack of complexity.

For example, in the data set below note that approximately 50% of test articles had appreciable effect on PR interval (atrial to ventricular conduction) – a parameter not even capable of interrogation in these cellular-based assays.

These ‘non-QT related’ findings can be as looming of a roadblock as lengthening of repolarization. The pharmacists’ shelf carries a number of compounds that are known for PR prolongation, most notably the recent anti-virals such as rotinavir and more seasoned medicines like the tricyclic antidepressants. An August 2009 Journal of the American Medical Association study has demonstrated that even slight PR interval prolongation is associated with an increase in atrial fibrillation and all-cause mortality.

Of additional interest, only 20% of the compounds showed potential liability for QT interval prolongation. Given the impetus for conducting these assays, this suggests a high propensity for false positivity with interrogation of I_Kr anatagonism alone.

This scenario has been played out in project team meetings countless times. “We have a ‘hit’ in the ion channel assay, why does the isolated heart [or in vivo assay] not translate?”

This reasoning is folly; we’ve lost our way in the quest for faster, cheaper methods to get a clinical candidate. Far fewer of our colleagues ask the related, more appropriate question; “We have a clean signal in the whole heart [or in vivo] approach, why is there a signal in the ion channel assay?” The answer is, of course, identical in both scenarios. However, the latter approach demonstrates a more reasonable grasp on the science behind the conduct of the assays.

The integrative approach is infinitely more complicated than a single ion channel or cell type. The more reasonable paradigm limits the sometimes misleading influence of relying entirely on these simple assays. They have a role in the testing funnel. However, without complementary interrogation, compounds not likely to have a clinical effect risk being unnecessarily de-prioritized.

QT Interval Not the Only CV Culprit

It’s no secret that unwanted cardiovascular toxicology is a leading cause of product withdrawals and update labeling. Over the years QT interval prolongation and proarrhythmia have become the likely culprits.

While these saboteurs are problematic, as researchers, they aren’t the only ones we should be investigating.

At CorDynamics, we had a hunch that if we took a data set of compounds accused of having some sort of positive cardiovascular finding we would find that changing cardiac pump function, QRS duration lengthening and PR interval prolongation are just as problematic to drug development programs. We were right as the graph below illustrates.

Recently a JAMA study backed up our findings and proved that PR interval prolongation, commonly known as first-degree atrioventricular block, is associated with significantly increased risks of atrial fibrillation, pacemaker implantation and, most importantly, all-cause mortality. Looking at our internal dataset above, almost 50% of novel test articles we work with in certain models have the propensity to delay atrioventricular conduction—the biomarker for which is long PR interval. As the JAMA article demonstrates, these unanticipated properties can be just as deadly.

It’s pretty simple. If you are developing a compound, you want to know of these potential effects. Don’t be afraid of the data—better to deal with these issues earlier, rather than in the clinic.

What’s the solution?

Interrogating cardiovascular effects early can greatly reduce late-stage compound attrition. I’ve always believed a robust testing funnel constructed to de-risk compounds early —using an integrative approach combining ion channel, isolated heart, and in vivo assessments —is the industry gold standard. Such an approach is not just good science, it’s good business too.