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.

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

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.

Catching Cardiotoxicity: Physiological Changes Can Precede Pathology

Time and again, we hear of compounds exhibiting cardiotoxicity well into the clinical stage of R&D and ultimately being pulled from the pipeline.

1. Were cardiovascular effects noticed early and not vetted properly?
2. Were there insufficient preclinical studies to find these indicators?
3. Or, did they not show up at all?

Any one of these three scenarios means millions if not billions of dollars wasted, not to mention the untold time spent advancing a doomed to fail compound through drug development. In case #’s 1 and 2, investing in a comprehensive battery of preclinical cardiovascular studies and following up on possible red flags can allow a sponsor to make critical go/no-go decisions early.

An example of this is outlined in a paper we recently co-published with Hoffman-La Roche in the British Journal of Pharmacology.

In standard two week toxicology studies, the compound RO5657- a CCR5 antagonist -had induced treatment related myocardial degeneration in previously normal animals. Employing a variety of preclinical models, the article demonstrated that the compound exhibited cardiovascular side effects and life threatening arrhythmias before the development of pathological findings. Thus, the change in cardiovascular physiology served as a harbinger of downstream histopathological events.

In fact, the ion channel and isolated heart interrogations conducted on RO5657 ultimately predicted the anesthetized, telemetry and toxicology study results. The sponsor was then able to use good scientific rationale to help make good business decisions on this compound.

How Preclinical Cardiovascular Anesthetized Data Translates into the Clinic

Translating preclinical cardiovascular data into clinical success is the name of the R&D game.

Anesthetized models are some of the most sensitive assays researchers can use to investigate the cardiovascular effects of their lead candidates and back-up compounds.

The thoroughly validated research and a wealth of scientific publications demonstrate that anesthetized studies in several subject species (canine, rat, guinea pig, rabbit, NHP) are highly predictive and similar to those observed in humans.

This is imperative as 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.

Anesthetized studies can be designed with advanced hemodynamics and electrophysiological testing to assess a variety of cardiovascular effects.

• Advanced hemodynamics
• Heart rate
• Systemic blood pressures
• Pulmonary artery pressure
• Left ventricular pressures and derivatives
• Cardiac output
• Blood flow
• PK/PD relationships
• Electrocardiograms

Armed with this critical data, developers can translate their preclinical results into strategies for improved clinical performance.

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.