Posts Tagged ‘Safety Pharmacology’

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

How to Conserve Test Article, Time and Money with Telemetry

Posted by CorDynamics on March 11th, 2014

Here’s a familiar dilemma. Your research team detects unanticipated cardiovascular activity in your lead candidate but there is limited test article for follow-up discovery and safety studies.

In these cases, we often suggest either conscious telemetry or an anesthetized preparation in the guinea pig as an effective model for cardiovascular testing, when appropriate. Since they are smaller in size, guinea pigs can serve as a 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 counterparts, such as rabbits.

The Conscious Model

Using telemetry to deliver quasi beat-to-beat data, this guinea pig model generates ultra high fidelity QT interval correction. View Conscious Validation Data

The Anesthetized Model

In this preparation, we employ a well-characterized anesthetized method to screen for cardiovascular effects early. Cardiovascular parameters such as blood pressure, heart rate, as well as ECG are measured and cardiac functional assessments can also be provided. View Anesthetized Validation Data

While a plus in terms of compound conservation, the guinea pig’s 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.

Although the guinea pig is not appropriate for every situation, 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.

Filed under: Drug Discovery Services, Drug Safety Services, 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

PAH Spotlight: Small Species with Dual Pressure Telemetry

Posted by CorDynamics on July 23rd, 2013

by Dr. Michael Gralinski, CorDynamics CEO

We continue to expand our capabilities in pulmonary arterial hypertension, and one thing is for certain: surgically instrumenting rats to measure systemic blood pressure AND pulmonary artery pressure—simultaneously—is an effective model for clients researching both prevention AND intervention of PAH.

To obtain continuous recording of pulmonary artery pressure, a telemetry catheter is placed into the pulmonary artery via the right ventricle. Post-recovery, the subjects are then exposed to classic PAH initiation agents such as monocrotaline or newer methods like hypoxia/semaxanib.

Measuring multiple pressures simultaneously allows our experts to differentiate test article effects on the pulmonary vasculature from those on the systemic circulation.

Up until recently, this level of in vivo telemetry instrumentation was only available in large animal models.

View Data Set #1

 View Data Set #2

Efficiency All-Around

At the risk of being obvious, the ability to measure multiple pressures clearly saves time and effort all around.

In addition, our low technical failure rate and clinical observations consistent with the development of robust pulmonary hypertension makes this an efficient option in terms of technician time as well as overall study deliverables.

As always, our models are designed with the 3R’s in mind. Collecting multiple variables from the same experimental subject reduces the need for redundant groups when separate pressures are interrogated.

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

Simultaneous Data Generation Connects Early Data to the Clinic

Posted by CorDynamics on May 22nd, 2013

Safety aspects have increasingly become an outstanding issue in the drug discovery and development arena with the FDA and the EMEA placing a clear emphasis on their importance.

The point is illustrated in the book Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays, co-authored by Dr. Franz Hock, CorDynamics European Business Development Director.

Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Sequential Development: The Paradigm of the Past

Up until 15 years ago, drug discovery and evaluation was a single, sequential process starting with the selection of the most active compound from a series of newly synthesized agents by means of special pharmacological assays.

• Safety aspects were addressed by pharmacological testing of the selected compound in high doses in assays directed at targets other than the intended indication of the new compound.

• These tests were followed by pharmacokinetic studies, which were mainly aimed at confirming a suitable half-life and oral activity.

• Safety aspects relied mostly on toxicity studies, which however gave information on changes of organ structure rather than on organ function.

• Toxicological and pharmacokinetic studies were adapted to the progress of studies in clinical pharmacology and clinical trials.

Simultaneous Data Generation: Today’s Paradigm

The sequential way of working has been replaced by simultaneous generation of data.

• Concurrent safety, pharmacodynamic and pharmacokinetic data is generated.

• If need be, bench-to-bedside and bedside-to-bench approaches can be facilitated to connect preclinical and clinical data as early as possible.

• Rather than a separation into toxicology, pharmacokinetics and clinical applications, a connectivity between all these disciplines is embraced.

This new paradigm is seen as mandatory in the eyes of regulatory bodies as well as among academic thought-leaders and drug development executives.

The industry as a whole has come to understand there is no real safety evaluation possible without combining toxicological, pharmacodynamic and pharmacokinetic data both from a preclinical and from a clinical environment.

To learn more on the topic or to order Dr. Hock’s book, click here.

 

Filed under: About Us, Drug Discovery Services, Drug Safety Services, Preclinical Consulting Services | 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

5 Signs Drug Development Outsourcing is In

Posted by Theresa Gralinski, Marketing Director at CorDynamics on November 14th, 2012

I spent most of last week at the American College of Toxicology meeting in Orlando taking the industry’s proverbial temperature.

Over the last four years this meeting’s attendees seemed concerned about feverishly downsizing, feverishly cutting budgets or feverishly outsourcing. People just didn’t feel well. This year attendees seemed to be “feeling” healthy and more optimistic.

Preclinical CRO Drug Development Outsourcing

I saw five clear signs that industry outsourcing is officially IN.

1. Back to Business—With mass waves of downsizing behind a number of our colleagues, clients and competitors, the focus of discussions turned to current programs and upcoming projects.

2. Changing Roles—Longtime  friends were embracing new positions, translating their pharma drug safety and drug discovery experience into success at virtual biotechs or contract research organizations.

3. New CROs and Consultants Join the Ranks—We welcomed new CROs to the “club” and I met with quite a few toxicologists who have decided to work as consultants to share their expertise to meet the anticipated demand.

4. Buzzwords—Collaboration. Customized. Experience. Responsive. Did I say collaboration?

5. Social Media…Really?—Admittedly the industry is still skeptical of the idea in a regulated industry. However with more drug developers looking for external services, vendors and CROs want to be easily found. (Shameless examples: cardiovascular CRO, prolonged QT interval, cardiovascular pharmacology.) Social media is a good way to get the message out.

I polled attendees on their comfort levels with the top social media platforms. Results: LinkedIn=Great; Blogging=Good; Twitter=So-So; Facebook=No Thanks.

Did you get a different temperature reading from the meeting? Or, did you sense a healthier optimism as well? Feel free to comment here or you can find me on Linkedin.

 

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

Preclinical Case Study: How to Investigate Hemodynamics and Cardiac Electrophysiology In Vivo

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on October 24th, 2012

The Case Study

Verrow Pharmaceuticals came to CorDynamics with an interesting cardiovascular safety question regarding their compound Veropaque. We came up with a customized study design leveraging our in vivo anesthetized canine model to generate answers.

The Question

Contrast products can cause significant kidney injury in about 10% of cardiology patients, resulting in contrast induced nephropathy. With Veropaque, Verrow hypothesized that the use of substituted cyclodextrins (SCD) in the formulation would mitigate the renal toxicity of a contrast agent (CA).

CorDynamics was enlisted to determine if Veropaque exhibited a hemodynamic and electrocardiographic profile similar to a marketed comparator in a relevant species.

The Answers

In our laboratories, we conducted in vivo anesthetized canine studies uniquely designed to monitor the cardiac hemodynamic and electrocardiographic effects of Veropaque.

View Data

Intracoronary artery injections in the dog revealed no significant differences between iohexol and Veropaque and no notable effects on most measured cardiovascular parameters other than transient changes in left ventricular contractility and QTc interval as previously described in the literature.

The resulting abstract, exhibiting at this week’s Transcatheter Cardiovascular Therapeutics Conference in Miami, illustrates that including substituted cyclodextrins in the formulation of a novel contrast agent is nephroprotective against contrast-induced acute kidney injury, functional changes, and mortality in rodent models without altering their cardiovascular profile.

 

Filed under: Anesthetized Models, Drug Safety Services, Electrophysiology, Hemodynamics, Preclinical Consulting Services, Telemetry | No Comments

How to Complete Two GLP Requirements in One Study: Respiratory Telemetry

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on October 17th, 2012

Clients with compounds poised for IND application are expected to conduct GLP (good laboratory practice) studies demonstrating drug safety in three areas.

Cardiovascular
• Respiratory
• Central Nervous System

With respiratory telemetry, we can now analyze two organ systems—cardiovascular and respiratory—with one large species study. Investing in this new technology is allowing us to help our clients meet their regulatory requirements within compressed timelines and finite budgets.

Our Telemetry Technology
Our Cardiopulmonary Transmitters (D70-PCTR developed by Data Sciences International) can be implemented in multiple large animal species. The telemetry system records respiratory parameters along with blood pressure and ECG simultaneously and continuously in conscious models.

Our Data
Our pharmacological validation data demonstrates the combined measurements captured with our respiratory telemetry. View data.

Measured, were the effects of bethanechol (a cholinergic agonist) on:
• Heart rate
• Tidal volume
• Minute volume
• Respiratory rate

In addition to saving our clients’ time and money, our telemetry studies also embrace the 3 R’s of animal welfare—replacement, refinement, reduction. This conservative approach is smart science and smart business.

Filed under: Drug Safety Services | No Comments

Preclinical Cardiovascular Safety Issues Signal Yield; Not Stop

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on July 26th, 2012

Obesity drugs are hot on the FDA radar this summer.

Approval of the Vivus weight loss drug Qsymia marks the second obesity treatment to survive the heat of preclinical cardiovascular safety scrutiny.

The Rollercoaster Ride to Approval
The FDA rejected Vivus’ first attempt at approval in 2010.
• The efficacy of Qsymia, a combination of two older approved drugs, appetite suppressant phentermine and antiseizure drug topiramate, was promising with patients losing more than 10 percent of total body.
• The safety concerns of Qsymia created the free fall. The FDA asked Vivus to go back and further investigate the cardiovascular safety of the compound —namely increased blood pressure and heart rates seen in the patient group. (Questions around the possibility for teratogenicity also needed further investigation.)
Vivus Heads Back to FDA Armed with Cardiovascular Safety Data in 2012.
• After completing a year-long clinical study, Vivus presented the FDA with in-depth cardiovascular data.
• While acknowledging potential cardiovascular effects, the FDA approves the new therapy with the following caveat: “Qsymia can increase heart rate; this drug’s effect on heart rate in patients at high risk for heart attack or stroke is not known. Therefore, the use of Qsymia in patients with recent (within the last six months) or unstable heart disease or stroke is not recommended. Regular monitoring of heart rate is recommended for all patients taking Qsymia, especially when starting Qsymia or increasing the dose.”
Qsymia Gains FDA Approval with Postmarketing Requirements.
• A long-term cardiovascular outcomes trial assessing the effect of Qsymia on the risk for major adverse cardiac events such as heart attack and stroke will be required by the FDA.
• The drug will also carry information on the label about potential for teratogenicity.

While the rollercoaster to approval for this drug was not for the feint of heart, it did prove that while the FDA will exercise caution in the face of cardiovascular risks, the agency will look at the big picture. If the benefits out-weigh the thoroughly investigated risks—the FDA is willing to give the drug a green light.

Filed under: Drug Safety Services, Preclinical Consulting Services | No Comments