Posts Tagged ‘Prolonged QT’

Cardio-Oncology: Where Safety Pharmacology Fits In

Posted by CorDynamics on June 23rd, 2015

Earlier this month I attended an excellent Safety Pharmacology Society regional meeting at Pfizer-La Jolla focused on cardio-oncology and safety pharmacology.

Dr. Lori Minasian, Chief of the Community Oncology and Prevention Trials Research Group Program and the National Cancer Institute of the National Institutes of Health (NIH), opened the conversation by reminding us we should feel some sense of accomplishment at being able to worry about the cardiovascular side effects of cancer treatment. She pointed out that in the not too distant past, chemotherapy had not generally been associated with levels of efficacy that would provide either time or a framework for such concern.

She pointed out that we are now in a new age where targeted and specific drugs are increasing survival with fewer toxic side effects – allowing us to have the “luxury” of holding such discussions. (Her clinician – and patient – perspective was a welcomed perspective that is often missing from these seminars and scientific meetings.)

Substantive data from case studies of compounds in this ‘new age’ were examined, including VEGF and MEK inhibitors among others.

In general we are concerned about downstream effects of hypertension and cardiac dysfunction, with a pinch of QT prolongation for good measure.  More on cardiovascular toxicity in cancer drugs.

The regulatory and industrial perspectives on how to handle these issues were covered at the meeting as well. Dr. Darrell Abernathy from the USFDA detailed thoughts on using a “systems pharmacology” approach for predicting and evaluating cardiac safety signals. Scientists from Pfizer and Novartis discussed their testing schemes that included preclinical models such as Langendorff isolated hearts, telemetry and echocardiography.

Promising Takeaways

  • The cardiovascular effects of these newer anti-cancer agents can be modeled in a preclinical fashion.
  • 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, Langendorff Heart, Preclinical Consulting Services, Telemetry | No Comments

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

Including CiPA in an Integrated Risk Assessment is a Welcomed Position

Posted by CorDynamics on September 22nd, 2014

Leveraging New Technology to Enhance Validated Techniques

by Dr. Michael Gralinski, CorDynamics CEO

I recently sat in on a Safety Pharmacology Society-sponsored webinar entitled “QT Assessments in Drug Development: Regulatory and Industry Perspectives”.

A combined FDA and industry perspective, most of the lecture was spent detailing the new approach to early screening for proarrhythmic potential – the CiPA (Comprehensive In Vitro Proarrhythmia Assessment) initiative. This is not the first time we’ve commented on CiPA. (Read previous blog: ILSI/HESI Proarrhythmia Paradigm Raises More Questions Than Answers.)  In the past I had felt reticent at best, but this discussion seemed to clear up some points of contention.

For the first time in the context of CiPA, the benefits of the complete preclinical integrated cardiovascular risk assessment were mentioned vis a vis decision making after a TQT trial.

Briefly, increased emphasis looks to be placed on early leveraging of in silico data – computer models of compound effects on ion channels and ventricular action potential electrophysiology. When this data is combined with high throughput counter screens against multiple cardiac ion channels – a more useful prediction could be in place compared to current high throughput approaches.

I was glad the authors mentioned interrogating the aforementioned data alongside other nascent/established cardiovascular assays and robust acute and chronic in vivo cardiovascular studies.

As we’ve discussed previously, too much emphasis on any single assay is a losing proposition over the long term. Data from past SPS president Dr. Derek Leishman’s part of the presentation described the failure of reduced compound advancement in this scenario.

We look forward to further discussion at the SPS and HESI meetings later this year.

Filed under: Cardiac Ion Channels, Drug Safety Services, Electrophysiology, Langendorff Heart, 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

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

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

World Rare Disease Day

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on February 29th, 2012

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.

Filed under: Press Releases, Pulmonary Arterial Hypertension | No Comments

The Short Story on Prolonged QT Interval

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on January 13th, 2012

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.

 

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