Cracking the Case on Sudden Cardiac Death and Domperidone

by Liomar Neves, Senior Scientist

Recently, the Journal of Cardiovascular Pharmacology published an original article investigating sudden cardiac death and QT interval prolongation associated with domperidone that caught the attention of our CorDynamics team.

The Report

Domperidone is a dopamine receptor antagonist not approved by FDA for sale in the US market, but is widely used in more than 100 countries. Its purported benefits are as a gastrointestinal prokinetic agent, an anti-nausea and vomiting therapeutic and more recently it has been used to promote lactation.

However, the compound has been associated with disturbances in ventricular electrophysiology. These include increases in QT interval and cardiac rhythm disturbances.

In this recent preclinical study, the authors confirm that domperidone prolongs action potential duration and suggests that the IC₅₀ for blocking the hERG channel I_Kr may be lower than previously reported.

New Evidence

The study also involved the use of prolonged domperidone exposure times, longer cycle lengths to examine reverse-use dependence, and use of rabbit hearts that are naturally heightened for sensitivity to I_Kr antagonism.

• Evidence demonstrated domperidone to have a high affinity to I_Kr and low safety margin, thus increasing risk of drug-induced long QT syndrome and potential proarrhythmogenesis.

• Additionally, the report brings attention to the limited benefits of domperidone for gastrointestinal disturbances and highlights the risk of using a low safety margin drug for a non-threatening target such as promotion of lactation.

The authors concluded the report by urging other regulatory agencies to take the FDA’s approach and ban domperidone’s use.

FDA Welcomes New Class of Diabetes Drugs

Invokana (canagliflozin) has been approved by the FDA for patients with Type II diabetes—with two cardiovascular caveats.

1. Leading up to approval, FDA reviewers highlighted the increased risk of cardiovascular problems to patients on the therapy as it lowered blood sugar but raised cholesterol in clinical trials.
2. A complete cardiovascular outcomes trial must be conducted.

Ivonkana is at the head of the new class of SGLT2 inhibitors.

These inhibitors block a protein associated with the reabsorption of glucose in kidneys to help diabetics clear blood sugars more efficiently.

“Invokana is the first diabetes treatment approved in a new class of drugs known as sodium-glucose co-transporter 2 (SGLT2) inhibitors,” said Mary Parks, M.D., director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “We continue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions that impact public health.”

In a statement regarding the approval of Invokana, the FDA is requesting five postmarketing studies for Invokana: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and two pediatric studies under the Pediatric Research Equity Act (PREA), including a pharmacokinetic and pharmacodynamic study and a safety and efficacy study.

FDA Rejects Xarelto for Second Time in Less Than a Year

The FDA rejected Xarelto (rivaroxaban) for a second time in less than a year as a drug therapy for patients with acute coronary syndromes.

Timeline of Concern

May 2012: By a narrow margin, an FDA Cardiovascular and Renal Drugs Advisory Panel recommended against expanding the marketing indications to prescribe Xarelto as an acute coronary syndrome therapy.

June 2012: The FDA confirmed panel opinion and denied expanding  Xarelto as an acute coronary syndrome therapy, citing concern over incomplete data.

• The gaps occurred after nearly 1,300 patients dropped out of 15,000+-subject final-phase study and withdrew consent for access to their health information. There were also notable concerns about bleeding risks – in the absence of antidote – for rivaroxaban.

March 2013: FDA rejects Xarelto bid sending a second “complete response letter” which infers even more data is again requested.

Fast Facts
• Xarelto (rivaroxaban) is a factor Xa inhibitor—a blood thinner. The drug is already approved for stroke in patients with nonvalvular atrial fibrillation. It’s also indicated for those undergoing joint replacement surgery to prevent deep vein thrombosis.
• Acute coronary syndrome (ACS) is a catch-all phrase referring to conditions involving coronary artery obstruction.
• The studies under review evaluated the safety and efficacy of rivaroxaban in more than 19,000 ACS patients in addition to aspirin with or without thienopyridine therapy.
• If the panel had advised approval it would have meant an endorsement of treating ACS patients with combination therapy (aspirin, thienopyridine and rivaroxaban).

What Does This Mean for Drug Developers?
The earlier potential cardiovascular questions can be answered the better.

Investing in thorough safety and efficacy studies from preclinical all the way through the clinical phases of drug development is key.

CorDynamics Sets Drug Discovery and Development 2013 Trade Show Calendar

The CorDynamics team is saying goodbye to a great 2012 and looking forward to more research and collaboration with colleagues in 2013. Closing one calendar and turning to a new one, some of the first dates to fill in are our trade show exhibitions.

As we continue to grow the early-stage drug discovery side of our business, we will again be visiting the Experimental Biology meeting in Boston, April 20-24. I look forward to attending this event and meeting with colleagues focused on linking drug discovery to development.

In addition to EB, we’ll also be exhibiting at SOT, SPS and ACT.

• Society of Toxicology 52nd Annual Meeting

San Antonio, Texas March 10-14

• 2013 Safety Pharmacology Society Annual Meeting

Rotterdam, The Netherlands September 16-19

• American College of Toxicology 34th Annual Meeting

San Antonio, Texas November 3-6

If you’re going to be at any of these meetings, please put us on your calendar.

Wishing you a very Healthy and Happy New Year.

Theresa Gralinski, Marketing Director

Zofran, The FDA and Return of Cardiovascular Culprit: QT Interval Prolongation

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.

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.

5 Signs Drug Development Outsourcing is In

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.

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.

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.

Timelines and Technology Drive Drug Development

Safety Pharmacology Society 2012 Meeting Reveals the “New Normal”

I’m on my way back from a trade show exhibit at the Safety Pharmacology Society meeting in Phoenix. Four days in the desert were filled with sessions, events as well as many friends and colleagues stopping by the CorDynamics booth to say hello.

It didn’t hurt that my business partner Peter Senese once again claimed the prime booth space—as greeter to all—right inside the exhibit hall entrance. We opened up with a vendor show where we were airing Monday Night Football live. A consistent group enjoyed the game over a beer or two, and shared insight into the current state of their organizations.

New Normal

Attendance was down a bit from previous meetings. The continuing consolidations, mergers, and belt-tightening by nature reduced the size of representation from more than a few companies. Nevertheless, the topic seemed to pass as the ‘new normal’ instead of being the focus as years before.

Positive Signs, Rational Approach to Forward Progress

Clients stopped by to discuss their unique drug development projects. Overall, their questions came down to two general categories.

1. Timelines—When can our new project be initiated? When can we expect results?
2. New Technology—Are CorDynamics’ new technologies generating solid data? How can we incorporate small animal dual pressure telemetry into our studies? Can we screen for cardiovascular liability in guinea pigs?

Leaving the plus 100-degree weather for the tempered fall of Chicago, we’re coming back with good feelings for the remainder of 2012. Happily, new projects continued to flow into the labs during our absence.

We look forward to next years’ SPS meeting in Rotterdam, Netherlands. Word is that Peter already claimed our lead-in booth space. Hope to see you there.

Who Regulates Drug Safety and Drug Development Better—the FDA or the EMA?

The answer: It depends on who you ask.

The FDA versus the EMA (European Medicines Agency) is a continual debate. Different analysts have different opinions that seemingly change weekly.

What is true, is that both the FDA and the EMA have:

• the tough job of regulating drug development to ensure the approval safe and effective therapies.
• their own set of policies, procedures and guidelines.
• their own governing bodies, growing bureaucracies and shrinking budgets.
• vigilantly regulated drug safety with a keen eye on cardiovascular safety.

Yet with all this in common, why do the FDA and EMA sometimes come to different conclusions?

Many say it’s because the healthcare environments are different between the US and Europe, as well as their vastly different legal systems.

Case Study #1: FDA Says Ok, EMA Says No Way
The weight loss drug, Qysmia, earned FDA approval in July. BUT, Qysmia’s sponsor expects the EMA to recommend against approval based on numerous concerns, including the effects of one of the drug’s two main ingredients, phentermine, and the link to possible heart valve damage.

Case Study #2: EMA Says Yes, FDA Says Not Yet
An advisory panel recently recommended approval of the new anti-clotting drug Eliquis. BUT, the FDA rejected the drug for the second time this past June, citing the need for more information.

What to do?
Outsource to contract research organizations experienced with the ins and outs of both agencies and their specific guidelines—especially when it comes to cardiovascular issues.

I know the FDA. Fortunately, my colleague, Dr. Franz Hock, knows the EMA. While neither of us is so bold as to claim the ability to predict FDA and EMA decisions, we do typically know what cardiovascular questions they will ask and what information they will need to make their decisions. Once you know that, finding the answers gets a bit easier.

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.