Posts Tagged ‘Risk Assessments’

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.

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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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