Posts Tagged ‘Oncology’

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

Investigating Cardiotoxicity in Anti-Cancer TK Inhibitor Class

Posted by CorDynamics on June 10th, 2014

Last week a story entitled The Serious Heart Risks That Come With Chemo was published in Time. The case studies detailed cardiac issues faced by cancer patients during and after (sometime years after) chemotherapy. The recognition of this phenomenon has spawned a new branch of cancer doctor, the cardio-oncologist.

The observation that both traditional and newer chemotherapeutics agents may interfere with heart function is not a new one. Doxorubicin’s relationship to drug-induced cardiomyopathy was first described in the 1970s and more recent publications have detailed the left ventricular dysfunction that may arise from imatinib, a tyrosine kinase inhibitor. Direct cardiotoxicity is not exclusive to these two compounds.

It is well established that cancer medicines can affect:

  • cardiac function
  • hypertension
  • electrocardiographic changes (including QT interval prolongation)

Most of these effects can be modeled in a preclinical fashion.

The mechanism behind heart failure associated with imatinib has been detailed in the research laboratory–leading to increased clinical vigilance along with improvement in treatment regimens.

Our laboratories have also investigated the cardiovascular changes with newer anti-cancer agents, most notably the TK inhibitor class. This mechanism attacks targets having a role in cancer growth or progression, while attempting to leave non-cancer cells alone. Sometimes however, both normal and cancer cells express the molecular target. Using telemetry, we have demonstrated the strong hypertension with TK inhibitors in chronic animal models.

View Data

These experiments have helped clients in their attempt to reduce unwanted cardiovascular toxicity.

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, Electrophysiology, 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

Beating Cancer Takes Heart

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

Without a healthy heart to sustain the human spirit, cancer wins.

In this light, it’s refreshing to see oncology researchers understand the importance of proactively gathering preclinical cardiovascular data.

As attendees of the American Society of Clinical Oncology meeting headed to Chicago, I took the opportunity to meet with several colleagues and clients to discuss their ongoing oncology projects.

A number of years ago, it was a fairly common industry practice within oncology development programs to provide nonclinical data from quite cursory examinations of unanticipated cardiovascular effects in support of new drug candidates.

Myth: Cancer patients have more consequential things to worry about than cardiovascular side effects.
In the past, the nonclinical cardiovascular battery consisted of actions on a single ion channel and the combination of in vivo cardiovascular assessment with a standard toxicology study. This was in contrast to the comprehensive risk assessments submitted for the more ‘traditional’ drug targets, such as depression or anti-infective agents, to name a few.

Truth: Preclinical data is crucial to driving the design of clinical trials in oncology programs.
We don’t want to be solving one problem now only to create others down the road.

If in vivo preclinical studies indicate some cardiac toxicity or reduced cardiac function, for example, this may warrant consideration of additional analyses such as echocardiograms or cardiac enzyme panels in the clinical program. (Learn More)

• In 2006, reports surfaced on the development of acute left ventricular dysfunction and heart failure in small numbers of patients taking imatinib (Gleevec) for the treatment of chronic myelogenous leukemia. Clinical oncologists are now armed with this information and appropriate safeguards can be instituted to reduce the likelihood of cardiotoxicity during dosing. (Learn More)

• More recently, we’ve begun to understand the basis for other unanticipated cancer pharmacology including the hypertension associated with vascular endothelial growth factor inhibition. Compounds, such as Avastin, Sutent, or Nexavar, work as anti-tumor agents by inhibiting the stimulation of blood vessels supporting malignant growth. They also happen to disrupt the nitric oxide pathway – a key process regulating mean arterial blood pressure. (Learn More)

Working together, I believe we can get to the heart of these matters and offer oncology therapies that change the face of the disease.

 

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

Cardiovascular Safety Studies Crucial for Oncology Drug Development

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on July 29th, 2011

I recently attended a Fierce Biotech webinar about Special Studies in Cancer Patients and Cardiac Safety. The presentation covered a wide range of solid information on cardiac safety as it relates to oncology clinical trials.

Time and again, we have clients wondering if they need to conduct thorough cardiovascular preclinical safety studies for oncology compounds. In most cases the answer is yes; and the panelists on the webinar agreed.

In fact, as the panelists discussed, preclinical data is crucial to driving the design of clinical trials in oncology programs. If, for example, in vivo preclinical studies indicated some cardiac toxicity or reduced cardiac function, this may warrant consideration of additional analyses such as echocardiograms or cardiac enzyme panels in the clinical program.

Oftentimes in the past, the nonclinical cardiovascular battery for oncology agents consisted of actions on a single ion channel and an in vivo cardiovascular assessment along with standard toxicology studies. This was in contrast to the comprehensive risk assessments submitted for the more ‘traditional’ drug targets, such as depression or anti-infective agents, to name a few.

The overriding thought process behind these data packages could usually be distilled in project team meetings to somewhat misplaced logic in isolation, such as ‘it [the compound] is for cancer’ or ‘these patients usually have more consequential things to worry about than CV effects’.

While on some level those statements may occasionally be appropriate, recent events prove once again that the physiological processes controlling both cancerous and normal cells are not entirely discrete. These events also serve to demonstrate the unintended clinical consequences of truncated early development.

As one of the cardiology panelists noted – we need to be both efficient, yet cautious, in our design of oncology clinical trials regarding the issue of cardiac safety. Since we often don’t fully understand the off-target consequences of interfering with cancer mechanisms, it is prudent to provide as much useful information a priori (from preclinical studies) to rationally design these trials.

 

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Some Cancer Drugs Cause Cardiovascular Side Effects

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on October 24th, 2010

A number of years ago, it was a fairly common industry practice within oncology development programs to provide nonclinical data from quite cursory examinations of unanticipated cardiovascular effects in support of new drug candidates. Oftentimes, the nonclinical cardiovascular battery consisted of actions on a single ion channel and the combination of in vivo cardiovascular assessment with a standard toxicology study. This was in contrast to the comprehensive risk assessments submitted for the more ‘traditional’ drug targets, such as depression or anti-infective agents, to name a few. The overriding thought process behind these data packages could usually be distilled in project team meetings to somewhat misplaced logic in isolation, such as ‘it [the compound] is for cancer’ or ‘these patients usually have more consequential things to worry about than CV effects’.

While on some level those statements may occasionally be appropriate, recent events prove once again that the physiological processes controlling both cancerous and normal cells are not entirely unique. These events also serve to demonstrate the unintended clinical consequences of truncated early development.

In 2006, reports surfaced on the development of acute left ventricular dysfunction and heart failure in small numbers of patients taking imatinib (Gleevec) for the treatment of chronic myelogenous leukemia. Upon nonclinical mechanistic examination of imatinib’s direct effects on ventricular cardiomyocytes, it was discovered that the compound interfered with intracellular mitochondrial function. As such, imatinib is not classified as a negative inotropic agent but can be characterized as directly cardiotoxic – at least as it relates to left ventricular function – due to the decrease in hemodynamics upon repetitive exposure in the aforementioned patients. Medical oncologists are now armed with this information and appropriate safeguards can be instituted to reduce the likelihood of cardiotoxicity during dosing with imatinib. The literature also contains compelling reports of a structurally modified version of imatinib that does not interfere with cardiomyocyte mitochondria in vitro.

More recently, we’ve begun to understand the basis for other unanticipated cancer pharmacology including the hypertension associated with vascular endothelial growth factor inhibition. Compounds, such as Avastin, Sutent, or Nexavar, work as anti-tumor agents by inhibiting the stimulation of blood vessels supporting malignant growth. They also happen to disrupt the nitric oxide pathway – a key process regulating mean arterial blood pressure.

While some of these toxicities likely could not have been predicted via traditional nonclinical activities, the operating philosophy that certain targeted pharmacology or therapeutic areas may require less robust major organ system interrogations can have unfortunate consequences. At the very least, it reduces the opportunity to vet the possibility of these side effects. For example, the increase in survival following some of the recent advances in oncology treatment needs to be considered in the context of lasting cardiovascular effects.

We don’t want to be solving one problem now only to create others down the road. It’s well recognized that this is easier said than done – but at the very least it needs to be kept in mind during the strive for balance between efficacy and safety in this challenging therapeutic area.

 

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