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Predicting Drug Toxicity for Acute Cardiac Events

Reporter: Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/?p=10679/Predicting Drug Toxicity for Acute Cardiac Events

Pharmaceuticals Dilemma

The pharmaceutical industry has, as the clinical diagnostics industry, consolidated, and seen new entries that are at some time merged into an established giant, needing resources to grow.  In the past, it was considered essential for a scientific commercial entity to invest at least 8 percent of budget to R&D.   However, the cost of manufacturing has gone down, but a large part of the budget outside of manufacture has to be taken up with, maybe a few exceptions, development, validation in clinical trials, and marketing.  This leaves the situation precarious without a basic research base, and has lead to consortia between academic centers, the federal governmant, and the industries.  I can’t venture into the role of Wall Street Investment and Venture Capital in the process of innovation, proprietary rights to discoveries, and viability.  A large problem they encounter really comes down to complexity of the biomedical reality, that keeps peeling off layers like an onion, exposing new problems to deal with.  As a result, we have seen repeated recalls of drugs that were blockbusters, over the last 2 decades.  To date, every “miracle” drug to manage sepsis and the several cardiac related drugs have  resulted in unexpected toxicities.
One of the leading causes of drug attrition during development is cardiac toxicity, which has a serious impact on cost and can impact getting new drugs to patients. Detecting cardiovascular safety issues earlier in the drug development program

• would produce significant benefits for pharmaceutical companies and, ultimately, public health, but
  • the reduction of therapeutic toxicities will not be easy and depends on the
  • emergence of genomic-based personalized medicine.

Comprehensive cardiovascular and electrophysiology assessments are routinely conducted in vivo and in vitro early in the preclinical or lead optimization phases of drug development. For example,

• the isolated perfused guinea pig heart preparation (classically called the Langendorff preparation)
• can be used to screen a series of related new chemical entities (NCE)

in the lead optimization phase for preliminary information on the relative effects on contractility and rhythm.
Additionally, intact animal non-GLP studies—generally conducted in anesthetized, non-recovery models—are designed to assess

• effects of NCEs on a range of acute hemodynamic and cardiac parameters such as
  • heart rate,
  • blood pressure,
  • electrocardiogram (ECG),
  • ventricular contractility,
  • vascular resistance,
  • cardiac output, etc.

These studies employ small numbers of animals, but may allow termination of research into NCEs with obvious cardiovascular side effects. These preparations also provide information on the involvement of the

• autonomic nervous system in the cardiovascular responses of the NCE.

Such effects can be important determinants in the total cardiovascular response to an NCE, and this information cannot be obtained with any known in vitro method.
But what if there are dangers that are not predictable in the short term because of the time span under which the effects can be viewed? The effects themselves are a result of interactions between

• the drug,
• endothelial cell receptors,
• and/or imbalance in oxidative stress promoters and suppressors,
• and involve signaling pathways.

That is a difficult challenge that may only be realized

• by rapidly advancing knowledge at the molecular cell level.

The ICH S7A and ICH S7B guidelines provide

• guidance on important physiological systems and
• assessment of pharmaceuticals on
  • ventricular repolarization and
  • proarrhythmic risk.

The guidelines were designed to protect patients from potential adverse effects of pharmaceuticals. Since these guidelines were issued in 2000 and 2005, respectively,

• cardiac safety study designs have been realigned
• to identify potential concerns prior to administering the first dose to humans.

It is now routine for all NCEs to be evaluated using an

• in vitro Ikr assay such as the hERG voltage patch clamp assay to assess for
  • the potential for QT interval prolongation.

Systems have evolved to screen large numbers of compounds

• using automated high-throughput patch clamp systems early in the lead
• optimization/drug discovery phase.

This is a cost effective method for determining an initial go/no-go gate. Once a compound has progressed to

• the development phase, it can once again be assessed with the hERG assay
• utilizing the gold standard manual patch clamp assay.

If the NCE under investigation is a cardiovascular therapy, then

• pharmacological characterization should occur
• early in the lead development process.

In addition to the techniques just discussed,

• a variety of “disease models” are available to help determine
  • whether the NCE will be efficacious in a clinical setting.

However sound the in vitro data used in screening and selection process (e.g., receptor-binding studies),

• NCEs that have been shown to be active in at least one in vivo model (e.g,. salt-sensitive Dahl rat model)
• have a higher likelihood of clinical success.

Once a lead is identified, it should still go through the generalized safety characterization discussed earlier.
The in vivo study designs for NCEs reaching the development phase to support the Investigational New Drug (IND) application (just prior to the first human dose) require acquisition of

1. heart rate,
2. blood pressure, and
3. ECG data

• using an appropriate species
• at and above clinically relevant doses.

The trend in the industry for these regulatory-driven studies has been to

• utilize animals surgically instrumented with telemetry devices that
• can acquire the required parameters.

The advantage of using instrumented animals over anesthetized animals is that

• data can be acquired from freely moving animals over greater periods of time
• without anesthetic in the test system,
  • which has the potential to confound and perturb results interpretation.

Appropriate dose selection relative to those used in the clinic provides valuable information about

• potential acute cardiac events and
• how they may impact trial participants.

The obvious limitation here is that the method of observation is essentially

• the same or less than that which is used in clinical practice,
• relying mainly on classical physiology to detect
  • inherently deep seated processes.

But it is not the same scale of issue as for the patient emergently presenting to the ED. Despite enormous efforts to reduce the development of and the complications of acute ischemia related cardiac events,

the accurate diagnosis of the patient presenting to the emergency room is still, as always, reliant on

• clinical history,
• physical examination,
• effective use of the laboratory, and
• increasingly helpful imaging technology.

and age, sex, diet, and ability to carry out the activities of daily living before treatment and 6 months to a year after discharge are relevant.

The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. There will be more to say about this.
Animal studies
Telemetry-instrumented animals can be used as screening tools earlier in the drug selection phase. Colonies of animals that can be reused, following a suitable wash-out period,
provide an excellent resource for screening compounds to detect unwanted side effects. The use of these animals

• coupled with
• recent advances in software-analysis systems allow for rapid data turnaround,
  • enables scientists to quickly determine if there are any potentially unwanted signals.

If any effects are detected on, for example, blood pressure or QT interval, then the decision to

• either shelve the drug or
• conduct additional studies

can be made before advancing any further in the developmental phase.   While this is very good for observing large effects, is it really sufficient for avoidance of late phase failure?

Interestingly, the experience that has been acquired since the approval of the ICH guidelines

• has allowed pharmaceutical companies to temper their response to finding a potentially unwanted signal.
• Rather than permanently shelve libraries of compounds that, for example, were
• found to be positive in the hERG assay—common practice when the 2005 guidelines came into being—
  • companies can now determine a risk potential based on knowledge gained with the intact animal studies.

Similarly, if changes in hemodynamic parameters are detected, there are follow-up experiments employing anesthetized or telemetry models that include additional measurements like

left ventricular pressure.
These experiments can be utilized to further assess their potential clinical impact
by examining effects on
myocardial contractility,
relaxation, and
conduction velocity.
These techniques primarily address acute effects: those following a single exposure.
Chronic effects—those seen with long-term administration of the NCE to an intact organism—are difficult to obtain in early development, but are routinely monitored during safety studies,
are conducted non-clinically during Phase 1 and 2 of the development process.

• ECGs typically are collected to evaluate the chronic cardiac effects in non-rodent species during these studies. It is recommended that
  • JET (jacketed external telemetry) techniques, which permit the recording of ECG’s—
  • but not blood pressure—

be applied in freely moving animals. If chronic effects are discovered,

• follow-up experiments can be conducted with any of the techniques mentioned in this article.

As the focus on cardiac safety has matured over the last 10 years, the Safety Pharmacology Society has led efforts to establish an approach

• to determine best practices for conducting key preclinical cardiovascular assessments in drug development.
•  to provide sensitive preclinical assays that can detect high-probability safety concerns.

Parallel efforts have been made to more accurately assess the translation of preclinical cardiovascular data into

• clinical outcomes and
• to encourage collaborations
  • between preclinical and clinical scientists involved in cardiac safety assessment.

This has been conducted under the umbrella of the International Life Science Institute–Health and Environmental Services Institute (ILSI-HESI) consortium, which has bought together

• industrial,
• academic, and
• government scientists
  • to discuss and determine what steps are necessary
  • to establish an integrated cardiovascular safety assessment program.

The goal is to provide better ways of predicting potential adverse events, allowing for earlier detection of cardiovascular safety issues and reducing the number of clinical trial failures.
http://www.dddmag.com/articles/2012/08/predicting-potential-cardiac-events?et_cid=2816494&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2farticles%2f2012%2f08%2fpredicting-potential-cardiac-events.

A recent poster presentation I think makes a good statement of advances that should move us forward:

http://www.biotechniques.com/multimedia/archive/00178/BTN_0311-March_Post_178205a.pdf

Another possibility is genetic testing to determine the likelihood of stroke, for example Corus CAD is

• a shoebox-size kit that uses a simple blood draw to measure the RNA levels of 23 genes.
•  it creates an algorrhytm-based score that determines the likelihood that a patient has obstructive coronary artery disease.

http://pharmaceuticalintelligence.com/2012/08/14/obstructive-coronary-artery-disease-diagnosed-by-rna-levels-of-23-genes-cardiodx-heart-disease-test-wins-medicare-coverage/
“By providing Medicare beneficiaries access to Corus CAD, this coverage decision enables patients to avoid unnecessary procedures and risks associated with cardiac imaging and elective invasive angiography, while helping payers address an area of significant healthcare spending,” CardioDx President and CEO David Levison said in a press release.
This discussion will be followed with a discussion of the evaluation of the patient acutely presenting with symptoms and signs that are suggestive of either acute pulmonary or cardiac disease, or both, that may be suggestive of a non ST elevation AMI. It becomes more difficult if ST depression or T-wave inversion is not detected.
Related articles
Obstructive Coronary Artery Disease diagnosed by RNA levels of 23 genes – CardioDx, a Pioneer in the Field of Cardiovascular Genomic Diagnostics
http://pharmaceuticalintelligence.com/2012/08/14/obstructive-coronary-artery-disease-diagnosed-by-rna-levels-of-23-genes-cardiodx-heart-disease-test-wins-medicare-coverage/

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