Posts Tagged ‘QT Interval’

Questioning QT Interval Measurements? Look at the Anesthetic: Part 2

Posted by CorDynamics on March 16th, 2015

QT Questions Look at Anesthetic

CorDynamics will be presenting a poster at the upcoming 2015 Society of Toxicology meeting in San Diego entitled: The Differential Effect of Nembutal and Ketamine/Xylazine Anesthetic on Dofetilide-Induced QT Interval Prolongation. 

The objective was to advance upon our previous findings presented at SOT last year. (Read Part I: When Questioning QT Interval Measurements: Look at the Anesthetic.) This model examines the effects of dofetilide, an IKr antagonist known to prolong QT interval, on guinea pigs anesthetized with either Nembutal or ketamine/xylazine.

The anesthetized guinea pig is a widely used model for early screening of drug-candidate effects on cardiovascular function. This species also continues to gain traction for use in conscious telemetry screening.

In this study, we found that administration of dofetilide to either Nembutal or ketamine/xylazine anesthetized guinea pigs significantly increased QTcB interval at all doses tested compared to time-matched vehicle control. QTcB interval increased up to 22% in the Nembutal group, yet only reached 12% in the ketamine/xylazine group even though the dose was increased 5-fold in the latter cohort. There were no effects on mean arterial pressure, heart rate, or other ECG parameters in either group.

View Poster

Our data demonstrate that sodium pentobarbital anesthetized guinea pigs are more sensitive to QTc interval prolongation than ketamine/xylazine animals.

Our Conclusion

Consideration should be taken when selecting anesthetics for the guinea pig cardiovascular model. Sodium pentobarbital should be the anesthetic of choice when screening compounds for the potential to prolong QTc interval.

Filed under: Anesthetized Models, Telemetry | No Comments

Investigating Cardiotoxicity in Anti-Cancer TK Inhibitor Class

Posted by CorDynamics on June 10th, 2014

Last week a story entitled The Serious Heart Risks That Come With Chemo was published in Time. The case studies detailed cardiac issues faced by cancer patients during and after (sometime years after) chemotherapy. The recognition of this phenomenon has spawned a new branch of cancer doctor, the cardio-oncologist.

The observation that both traditional and newer chemotherapeutics agents may interfere with heart function is not a new one. Doxorubicin’s relationship to drug-induced cardiomyopathy was first described in the 1970s and more recent publications have detailed the left ventricular dysfunction that may arise from imatinib, a tyrosine kinase inhibitor. Direct cardiotoxicity is not exclusive to these two compounds.

It is well established that cancer medicines can affect:

  • cardiac function
  • hypertension
  • electrocardiographic changes (including QT interval prolongation)

Most of these effects can be modeled in a preclinical fashion.

The mechanism behind heart failure associated with imatinib has been detailed in the research laboratory–leading to increased clinical vigilance along with improvement in treatment regimens.

Our laboratories have also investigated the cardiovascular changes with newer anti-cancer agents, most notably the TK inhibitor class. This mechanism attacks targets having a role in cancer growth or progression, while attempting to leave non-cancer cells alone. Sometimes however, both normal and cancer cells express the molecular target. Using telemetry, we have demonstrated the strong hypertension with TK inhibitors in chronic animal models.

View Data

These experiments have helped clients in their attempt to reduce unwanted cardiovascular toxicity.

The more we know about the multi-faceted profile of these agents, the better chance we have to simultaneously treat the disease while working to mitigate any side effects.

Filed under: Drug Safety Services, Electrophysiology, Telemetry | No Comments

When Questioning QT Interval Measurements: Look at the Anesthetic

Posted by CorDynamics on April 09th, 2014

QT Questions Look at Anesthetic

CorDynamics recently presented a poster at the 2014 Society of toxicology meeting in Phoenix entitled: Effect of Anesthetic on QT Interval Measurements in Guinea Pigs.

Our objective was to investigate the baseline vulnerability of the anesthetized guinea pig for safety pharmacology screening of drugs with the potential to prolong the QT interval.

The anesthetized guinea pig is a widely used model for early screening of drug-candidate effects on cardiovascular function. This species also continues to gain traction for use in conscious telemetry screening.

The vast majority of these cardiac safety studies are performed in anesthetized guinea pigs with sodium pentobarbital as the anesthetic of choice. However, it’s well documented that sodium pentobarbital is an antagonist of the inward rectifying cardiac potassium channel IKs. Since the IKs is a robust component of the guinea pig cardiac repolarization sequence, this species can be particularly sensitive to IKs blockade.

In this study we investigated the baseline vulnerability of the guinea pig anesthetized with ketamine and Nembutal for safety pharmacology screening of drugs with potential to prolong the QT interval.

View Poster

Our data demonstrated that the choice of anesthetic appears to influence the QT interval in anesthetized guinea pigs compared to conscious animals.

Our Conclusion

It is possible that anesthetics with additional inherent IKs blockade such as sodium pentobarbital may overly sensitize the animal to agents that prolong the electrocardiographic QT interval. Consideration should be taken when selecting anesthetics for this model.

Filed under: Anesthetized Models, Drug Safety Services | 1 Comment

CorDynamics to Showcase Cardiovascular Capabilities at SPS 2013

Posted by CorDynamics on September 10th, 2013

CorDynamics heads to Rotterdam for the Safety Pharmacology Society meeting next week, September 16-19th.

Peter Senese, CorDynamics co-founder and chief operating officer, along with Dr. Franz Hock, our European business developer will be on hand in The Netherlands to discuss cardiovascular safety assessments and capabilities:

• Telemetry—dual pressure, respiratory parameters, ECG

• Isolated Langendorff heart

• Electrophysiology, hemodynamics

Of special note, we will also be featuring the latest industry primer: Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays co-edited by Dr. Franz Hock.Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Among a number of hot topics, the book argues the days of sequential drug development should be a thing of the past, replaced instead with simultaneous data generation combining toxicological, pharmacodynamic and pharmacokinetic data both from a preclinical and clinical environment.

To discuss these topics and more, please stop by our booth. If you’re not attending this year, feel free to contact us for more information.

 

Filed under: Drug Safety Services, Electrophysiology, Hemodynamics, Langendorff Heart, Telemetry | No Comments

ILSI/HESI Proarrhythmia Paradigm Raises More Questions Than Answers

Posted by CorDynamics on September 05th, 2013

At the end of July 2013, ILSI/HESI co-sponsored a meeting in Washington D.C. along with the Cardiac Safety Research Consortium / USFDA entitled “Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment during Drug Development without the Thorough QT Study”.

Essentially, the agenda was a discussion of the ‘paradigm shift’ and ‘proposed testing schema’ under consideration to improve the cardiovascular risk assessment of new chemical entities submitted for marketing licensing. The scheduling of the meeting indicates dissatisfaction, either perceived or real, with the current cardiovascular safety testing funnel.

I was not at the meeting due to a calendar conflict. Although I was frustrated as the topic is certainly germane to our business interests, the organizers posted the presentations and slides online. In hindsight, viewing the slides objectively unencumbered by discussions and sidebars gave me an unfiltered look.

After further view, I found the arguments to contradict one another. On one hand, the presentation highlighted potential consequences of not changing the current testing scheme as: the ‘perversion of lead selection’ and ‘NOT fulfilling the public health need.’ However, the presenters also stated there have been ‘no QT-related withdrawals’ and ‘reductions in post-marketing reports of arrhythmias’ as evidenced by E14 and S7B successes.

Frankly, which is it? Aren’t the reduction of QT-related withdrawals and reduction in post-marketing reports of arrhythmias fulfilling the public health need and informing drug developers who are making lead optimization decisions? Like most things it’s probably somewhere in the middle.

So, here are some questions:

1. If cardiovascular risk reduction has indeed improved – arguably the accurate metric of public health need – is the concern actually that the industry has become too conservative resulting in weak pipelines?

2. Where is the data demonstrating computer simulations of cardiac myocytes – or computer simulations of whole hearts–are more complex and integrative than in vitro or in vivo proarrhythmia models? With what information are these computer simulations being programmed? I would argue the animal models, when designed appropriately, likely contain the vulnerable substrate(s) similar to the susceptible population (the public) necessary to facilitate or induce triggered arrhythmias.

3. Speaking of proarrhythmia— what happened to the examination of in vivo proarrhythmia models? Is the database and methodology accrued over 30+ years just considered too complex with too few people to understand it?

4. The oft-used descriptor of the hERG assay’s potential as a red herring is that ‘many of the 100 most-prescribed drugs are hERG blockers’. Is somebody testing the 100 most-prescribed drugs in stem cells and in silico models? Are the results any different?

There are questions sure to be discussed vociferously in the months ahead.

The slide deck from the investment community representative makes the most sense at face value.

• Reduce uncertainly as far and as early as possible

• Make test batteries efficient and effective

• Create international benchmarks

Ironically, these were the exact same calls to arms for generating ICH S7A, S7B, and E14 in 2000 and 2005.

 

Filed under: Cardiac Ion Channels, Drug Safety Services, Electrophysiology, Langendorff Heart, Telemetry | 2 Comments

Cracking the Case on Sudden Cardiac Death and Domperidone

Posted by CorDynamics on April 18th, 2013

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 IKr 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 IKr antagonism.

  • Evidence demonstrated domperidone to have a high affinity to IKr 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.

Filed under: Cardiac Ion Channels, Drug Safety Services, Electrophysiology, Langendorff Heart | No Comments

FDA Warns Azithromycin May Prolong QT Interval

Posted by CorDynamics on March 19th, 2013

Azithromycin_QTINterval_Warning_FDAIt’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.

Filed under: Drug Safety Services, Langendorff Heart, Telemetry | No Comments

Validated Anesthetized Model Screens Cardiovascular Effects Early

Posted by CorDynamics on January 31st, 2013

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.

Filed under: Anesthetized Models, Drug Safety Services, Electrophysiology, Hemodynamics | 1 Comment

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

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on December 05th, 2012

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.

Cardiovascular Safety Studies Find QT Interval Prolongation

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.

Filed under: Drug Safety Services, Electrophysiology, Hemodynamics, Langendorff Heart, Telemetry | No Comments

The Case for Cardiovascular Safety Studies

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on July 10th, 2012

What Drug Developers Need to Know….

Case for Cardiovascular Safety Studies

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.

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

Filed under: Anesthetized Models, Cardiac Ion Channels, Drug Safety Services, Langendorff Heart, Telemetry | No Comments