Posts Tagged ‘Safety Pharmacology Society’

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

Does the FDA Refer to Disease-State Models to Determine Safety?

Posted by CorDynamics on April 22nd, 2015

The answer is: sometimes.

FDA Orphan Drugs Rare Diseases Cholesterol

A few months ago I attended an excellent Safety Pharmacology Society webinar (Nov 2014, “Cardiac Safety Testing Models”) where the non-clinical examination of cardiac contractility was discussed.

Dr. Philip Gatti, from the US FDA, concluded that compounds with putative inotropic effects should undergo “better utilization of in vitro systems (Langendorff or wedge preps) or use of animal models of heart failure which would enhance sensitivity to such drug effects.

Our labs have interrogated the cardiovascular effects of test articles in a variety of underlying pathophysiological states, including subjects with hypertension to those with impaired respiratory capacity.

One of the more frequent drug safety conditions we are asked to model is the compromised or failing heart. Many project teams need to know if their compounds affect left ventricular hemodynamics in the presence of pre-existing cardiac dysfunction. Sometimes these properties may not exist in the normal subject. However, they may be present in the target population.

We have conducted these studies using multiple models, including the post-infarcted heart, hypertrophy following hemodynamic overload (such as transverse aortic constriction), and tachypaced-induced cardiomyopathy.

Similar questions are usually asked:

  • Is it appropriate to examine drug safety in animals with ‘disease-state’?
  • Is this a current regulatory expectation?
  • Is there a differential effect compared to ‘normal’ animals?

Using these approaches, we have uncovered substantive areas of concern while also mitigating issues that previously appeared insurmountable.

We know there is an important role for using the ‘disease-state’ subject in cardiovascular safety pharmacology assessments.

While most preclinical studies will continue to use normal animals for risk assessment, the inclusion of disease models where appropriate can help unmask notable toxicities that may only occur in the target patient population.

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

Multiple Models for Researching the Complexities of PAH

Posted by CorDynamics on November 06th, 2014

To state it simply, pulmonary arterial hypertension is a complex disease.

Our labs have generated substantive data, and after numerous conversations with colleagues, it is clear that researching this disease from multiple aspects is likely the most efficient way to help find new treatments.

We recently presented a comprehensive overview of our PAH findings at a Lunch and Learn at the 2014 Safety Pharmacology Society Annual meeting and again for a client project team.

new_therapies_for_PAH

VIEW PRESENTATION

Over the past several years, companies were focused on providing benefit to PAH patients primarily through a hemodynamic mechanism such as selective pulmonary arterial vasodilation. Recently, the paradigm has shifted to focus more on the remodeling and inflammatory processes associated with the development of PAH.

Although the hypoxia / VEGF antagonist treated rat continues to be the gold standard animal model of this disease, increasingly we have been conducting experiments using a T-cell deficient rat co-treated with VEGF antagonist. This model is dependent on dysregulated immunity contributing to increased inflammation that exacerbates PAH.

Our results showing a protective effect with the LTA4 hydrolase inhibitor bestatin are consistent with the literature. In addition, we now have data demonstrating that sildenafil (PDE5 inhibitor – hemodynamic effect) shows efficacy in this ‘inflammatory’ model as well. A recent article has also shown that sildenafil has an anti-inflammatory effect in monocrotaline treated rats.

Research into developing additional and better treatments for PAH continues at a rapid and growing rate. We are also discovering new mechanisms by which current options exert efficacy. By continuing to refine the animal models of this disease, we stack the odds of success in our favor.

Filed under: Drug Discovery Services, Drug Safety Services, Pulmonary Arterial Hypertension | No Comments

PAH Data Download: The Ins and Outs of Multiple Models

Posted by CorDynamics on October 15th, 2014

Over the past 5 years our laboratories have conducted numerous studies with various models of pulmonary hypertension.

We are looking forward to sharing some our findings next week at the Safety Pharmacology Society Annual meeting in Washington, D.C. in a lunch and learn on Monday, October 20th.

We will be discussing results from our monocrotaline and hypoxia experiments as well as sharing our large datasets generated from clinical treatments in our gold standard model–the hypoxia/VEGF receptor antagonist exposed rat.  These results are very compelling – and show differential effects of sildenafil at 3, 4, 6 and 12 weeks into the hypoxia/VEGF model.

Slide2

Over the past year, our labs have also conducted studies with an alternative preclinical model of PAH – the athymic nude rat treated with VEGF receptor antagonist. This model may be applicable to a certain subset of PAH patients where inflammation appears to play a major pathogenic role.

If you are at SPS – stop over for some lunch accompanied by an in depth data dissection from various models of pulmonary arterial hypertension.

For those that are not attending – check our website after the SPS meeting where you’ll be able to download the slide deck from our presentation.

Filed under: Drug Discovery Services, Drug Safety Services, Pulmonary Arterial Hypertension | 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

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

CorDynamics Sets Drug Discovery and Development 2013 Trade Show Calendar

Posted by Theresa Gralinski, Marketing Director at CorDynamics on December 19th, 2012

The CorDynamics team is saying goodbye to a great 2012 and looking forward to more research and collaboration with colleagues in 2013. Closing one calendar and turning to a new one, some of the first dates to fill in are our trade show exhibitions.

As we continue to grow the early-stage drug discovery side of our business, we will again be visiting the Experimental Biology meeting in Boston, April 20-24. I look forward to attending this event and meeting with colleagues focused on linking drug discovery to development.

In addition to EB, we’ll also be exhibiting at SOT, SPS and ACT.

  • Society of Toxicology 52nd Annual Meeting

San Antonio, Texas March 10-14

  • 2013 Safety Pharmacology Society Annual Meeting

Rotterdam, The Netherlands September 16-19

  • American College of Toxicology 34th Annual Meeting

San Antonio, Texas November 3-6

If you’re going to be at any of these meetings, please put us on your calendar.

Wishing you a very Healthy and Happy New Year.

Theresa Gralinski, Marketing Director

Filed under: Drug Safety Services | 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

Timelines and Technology Drive Drug Development

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

Safety Pharmacology Society 2012 Meeting Reveals the “New Normal”

I’m on my way back from a trade show exhibit at the Safety Pharmacology Society meeting in Phoenix. Four days in the desert were filled with sessions, events as well as many friends and colleagues stopping by the CorDynamics booth to say hello.

It didn’t hurt that my business partner Peter Senese once again claimed the prime booth space—as greeter to all—right inside the exhibit hall entrance. We opened up with a vendor show where we were airing Monday Night Football live. A consistent group enjoyed the game over a beer or two, and shared insight into the current state of their organizations.

New Normal

Attendance was down a bit from previous meetings. The continuing consolidations, mergers, and belt-tightening by nature reduced the size of representation from more than a few companies. Nevertheless, the topic seemed to pass as the ‘new normal’ instead of being the focus as years before.

Positive Signs, Rational Approach to Forward Progress

Clients stopped by to discuss their unique drug development projects. Overall, their questions came down to two general categories.

  1. Timelines—When can our new project be initiated? When can we expect results?
  2. New Technology—Are CorDynamics’ new technologies generating solid data? How can we incorporate small animal dual pressure telemetry into our studies? Can we screen for cardiovascular liability in guinea pigs?

Leaving the plus 100-degree weather for the tempered fall of Chicago, we’re coming back with good feelings for the remainder of 2012. Happily, new projects continued to flow into the labs during our absence.

We look forward to next years’ SPS meeting in Rotterdam, Netherlands. Word is that Peter already claimed our lead-in booth space. Hope to see you there.

Filed under: Drug Discovery Services, Drug Safety Services, Langendorff Heart, Telemetry | 2 Comments

CorDynamics Sets Fall Conference Calendar: Safety Pharmacology Society and American Colllege of Toxicology

Posted by Theresa Gralinski, Marketing Director at CorDynamics on September 06th, 2012

With a great summer behind us, the CorDynamics team is looking ahead to a productive fall season and two upcoming trade shows.

2012 Safety Pharmacology 51st Annual Meeting in Phoenix (October 1-4)
With all the recent FDA decisions surrounding cardiovascular safety in everything from weight-loss compounds to hepatitis C therapies, this meeting will be the ideal place to discuss our cardiovascular safety pharmacology expertise with clients and colleagues.

2012 American College of Toxicology 33rd Annual Meeting in Orlando (November 4-7)
We will showcase our safety studies as well as our discovery models to demonstrate our ability to help clients translate preclinical data into greater pipeline predictability.

If you’re going to be at any of these meetings, please put connecting with us on your calendar.

If not, feel free to contact us–we’re always available to collaborate on your most pressing projects.

Filed under: Drug Discovery Services, Drug Safety Services | No Comments