Team:KU Leuven/HP/Gold Integrated

Human practices: Integrated and Gold

In HEKcite we create an oscillating HEK-cell, but for what purpose? Therapeutic drug monitoring is our answer. In the treatment of multiple severe diseases, a stable concentration of drugs is crucial. Steady blood levels determine therapeutic outcomes and increase survival rates. Currently, the most common therapeutic drug monitoring technique is blood sampling. For patients who need lifelong observation, the numerous hospital visits and frequent blood samplings can have a negative effect on the quality of life. Therefore, we develop a system that allows patients to determine the level of drugs at home. Furthermore, the ease of these measurements allows for daily or even continuous analysis.

Using this dynamic data collection instead of the static measurements performed in hospitals today, we might increase both therapeutic outcomes and quality of life of patients. In order to investigate the different views on our projects we talked to specialists in several fields where therapeutic drug monitoring is of great importance: transplantations, psychotics and epileptics. Three specialists have provided insights in how they expect our project will influence the lives of their patients and future treatments. We used this information to further shape our project.

Professor Diethard Monbaliu MD, PhD

Professor Monbaliu is a reputable abdominal transplant surgeon, at the department of microbiology and immunology at UZ Leuven. He is also responsible for a course on topographical and radiological anatomy and supervises several thesis students.

Professor Monbaliu confirmed our suspicion that there is a need for a more dynamic measurement. In addition, he suspects that it could lead to a better evaluation of patients’ compliance. Together, these advances could result in fewer transplant rejections. He has also brought our attention to a novel and more prevalent immunosuppressant drug, tacrolimus. Finally, he mentioned that patient variability is an issue in his field, and that our device should take this into account. Want to learn more? Press for more details.

Before this meeting, we were investigating the immunosuppressant cyclosporine, as we thought this compound was commonly used after transplantations in order to reduce the chance of rejection. However, professor Monbaliu clarified that this is no longer the case. Instead, he brought our attention to the compound tacrolimus, which has taken cyclosporine’s place in transplantation medicine. Both drugs have the same mode of action, but tacrolimus has a better clinical outcome and less side effects. We were interested in using this novel drug for our research, but unfortunately, the compound is too expensive for us to use. Therefore, considering our financial situation and the input of the professor, we chose to use cyclosporine in our experiments.

Lastly, according to professor Monbaliu, a possible reduction of blood sampling could be a great advantage. However, he mentioned that every patient is different, which means that finding the optimal concentration of immunosuppressant for each patient could a challenge. As a result, our device should be calibrated individually for every patient. Together with professor Monbaliu, we suspect that the individual differences and the problems that go with them could be assessed during clinical studies. As soon as different patients and their different values can be assembled, it can lead to the procedures needed to determine the optimal drug concentration and calibrate our device.

Professor Chris Bervoets MD, PhD

Professor Chris Bervoets is a psychiatrist. He is responsible for the department of transcranial magnetic stimulation, the department of deep brain stimulation and the department of compulsive disorders within the UPC (University Psychiatric Center) of KU Leuven. Additionally, he conducts research on neuromodulatory treatments for various psychiatric disorders.

While investigating different branches in medicine that could benefit from improved therapeutic drug monitoring, our attention was drawn to psychiatry. In this field, there are several drugs, for example lithium, that affect ion channels and could therefore be measured directly by our system. These aspects spiked our interest, and to learn more we contacted the specialist professor Chris Bervoets, who gave us some valuable insights in the difficult world of psychiatry.

After explaining our project, professor Bervoets shared his enthusiasm about the possible advantages of our device. He mentioned three ways in which HEKcite could further shape the field of psychiatry.

First of all, he described the current problems concerning treatments using dopamine antagonists. These dopamine antagonist are blockers of the so-called dopamine receptors, and are used for a wide range of psychologic disorders, among which are depression, psychosis, and many more. At present, researches lack detailed information about the correct dosage of these dopamine antagonists: The amount of receptors that have to be occupied to achieve a certain clinical effect is not yet known. In some cases, doctors see a more favourable clinical outcome when patients take dopamine antagonists irregularly, while for other patients, this is not the case. Therefore, a better understanding of how the correct dosage correlates with dopamine receptor occupancy could be extremely valuable.

Nowadays, this occupancy can only be measured using expensive PET scans. If we could find a way to insert the dopamine receptor in our HEKcite cells and genetically design a correlation of the electric rhythm and the occupancy of the receptors, it could generate valuable information concerning different drug concentrations and their corresponding receptor occupancies. Not only would this measurement be less expensive than a PET scan, it would also provide a more dynamic measurement of the receptor occupancy, which could result in additional insights in dopamine antagonist metabolism.

Furthermore, Chris Bervoets told us about a novel way of clinical assessment, called the experience sampling method (ESM). Patients are asked to answer ten or more questions a day regarding their emotional status. The answers to these questions are then used to improve diagnosis or foresee psychotic episodes. Professor Bervoets suggests that our device could complement this method by combining the answers of the patients with the exact drug concentrations at a certain time. This could lead to a better comprehension of the connection between symptoms and drug dosage, and help further treatments.

Finally, professor Bervoets mentioned safety monitoring, which was our original motivation to investigate the field of psychiatry. With our device, we could verify the concentration of certain drugs that only have a small therapeutic range in which they are effective. Furthermore, Professor Bervoets explained to us that lithium may cause side effects even in the right doses. As a result, many patients visit the hospital unnecessarily. Our device could prevent these avoidable hospital visits by reassuring the patient that the experienced symptoms are due to a benign lithium intoxication. On the other hand, it could also warn the patients when their lithium concentrations are dangerously high and a hospital visit is required.

After discussing these interesting possibilities for our project, we asked professor Bervoets if he thinks whether patients would accept to undergo the implantation of a small device. He suspects that our project would most likely only reach a select group of patients. For instance, patients who experience severe symptoms are often treated by transcranial magnetic stimulation and are used to medical interventions. This group of patients would not mind a minor subcutaneous implantation, if this would decrease their symptoms. Additionally, our device could help determine which drug is most suitable for a patient and optimise doses to reduce side effects.

To conclude, professor Bervoets confirmed our speculations that therapeutic drug monitoring is important in psychiatry. Furthermore, he opened our eyes to other potential applications of HEKcite in this branch of medicine and research. We are very interested in investigating the correlation of ESM and drug concentrations and the possibilities of developing a system to analyse dopamine antagonists. However, due to time and resource constraints, we have to remain focussed on therapeutic drug monitoring. Thanks to professor Bervoets’ enthusiasm about the project and the possible applications, we have become even more motivated to investigate the possibilities of safety monitoring, and believe it could bring science and medicine a substantial step closer towards solving important problems in psychiatry.

Professor Wim Van Paesschen MD, PhD

Professor Wim Van Paesschen is a neurologist specialized in epilepsy. He also is head of the epilepsy research laboratory of the UZ Leuven, and is a lecturer at the faculty of medicine.

Professor Van Paesschen confirmed that therapeutic drug monitoring is important for anti-epileptic compounds and mentioned the necessity of verifying patient compliance. He was very enthusiastic about the project, and even suggested other possible applications for the HEKcite cells.

As our group focuses on drug monitoring as an application, anti-epileptic drugs seemed to be interesting to research. Therefore, we set a meeting with doctor and neurologist Wim Van Paesschen, who is a specialist in epilepsy. Our goal was to discuss the importance of drug monitoring for patients being treated from epilepsy, and whether the HEKcite project could be useful in this regard.

During the meeting, professor Van Paesschen showed a great deal of excitement and enthusiasm about the project, and assured us that drug monitoring of anti-epileptics is indeed necessary, especially for patients who suffer from severe forms of epilepsy. There have been various attempts to introduce therapeutic drug monitoring for epilepsy patients, but none have been successful so far.

Since the concept of HEKcite mainly relies on different ion channels, professor Van Paesschen advices us to focus on the anti-epileptic compounds that directly influence ion channels, even though they are not the most commonly used. Some examples are retigabine, which opens potassium channels, and ethosuximide, which influences T-type calcium channels. Additionally, he mentions that some anti-epileptics can bind to the blood protein albumin, which hinders their activity. Laboratory tests can only measure the total concentration of anti-epileptics in the blood, and are unable to detect the amount of free, active compound. Using our system, we would measure the concentration of free drugs that are able to interact with the ion channels in vivo, which would be a great advantage.

Furthermore, we asked professor Van Paesschen whether he thinks patients would agree with an inserted monitoring device. He proceeded to say that biosensing is a very interesting and growing field, and that it would be most welcome by patients, due to its simplicity and accuracy. He also mentions that checking patients’ compliance is crucial for epilepsy treatment, and that the HEKcite project could be used to solve that problem.

Last but not least, he gave a few suggestions for other useful applications of the HEKcite project. First of all, he suggested using our system as a form of personalized medicine. By using ion channels that contain the exact mutation present in the patient, we could use our system to verify which drug is most effective for his or her exact condition. Additionally, he mentioned that epilepsy is often the result of multiple mutations in several channels. Our system could study the interactions between the different ion channels and their mutations to further improve the understanding of the mechanisms that can lead to epilepsy.

These examples further illustrate that the project could be used for multiple applications. All in all, the meeting was extremely helpful to us, as he was able to confirm our suspicions that HEKcite could be useful for patients of epilepsy, and shed some more light on the further possibilities within this field.

Professor Peter Sinnaeve MD, PhD

Prof. Dr. Peter Sinnaeve is a cardiologist who is specialized in acute cardiology, intensive care cardiology, interventional cardiology and pericardium disorders. Next to this, he is a part-time teacher at the Faculty of Medicine of KU Leuven.

After our meeting with professor Sinnaeve we learned that therapeutic drug monitoring of ivabradine is not clinically relevant within the field of cardiology. However professor Sinnaeve reassured us that using ivabradine as a proof-of-concept is still valuable. Next to this, he mentioned the crucial value our project could have in measuring drug concentrations during phase 1 clinical trials where a strict follow-up and good patient compliance is of great importance.

Looking at the three ion channels we introduced, the mHCN2 channel is the most crucial one to establish an intrinsic rhythm in HEK cells. When researching possible drugs that could inhibit or stimulate the mHCN2 channel, we discovered an important antagonist: ivabradine. When beta blockers are no longer sufficient for the symptomatic management of stable heart related chest pain or heart failure, ivabradine is prescribed.

After doing some experiments with ivabradine as a possible substrate to change the electrical rhythm of the HEK cells, we wanted to establish if therapeutic drug monitoring of ivabradine is indeed necessary. Therefore, we scheduled a meeting with cardiologist Peter Sinnaeve. He made us realize that we overlooked a simple and commonly used marker for ivabradine monitoring, namely the heart rhythm itself. Ivabradine’s function is lowering the heart rate hence making the heart a direct read-out of the effectivity of the drug. This means that there is no medical need for therapeutic drug monitoring of ivabradine. However, dr. Sinnaeve reassured us that using ivabradine as a proof-of-concept, to show that the rhythm can be changed, would be fitting.

These insights made us wonder if there are other possible applications of our device in cardiology. One of the biggest problems in cardiology is the burden on society caused by the numerous patients with heart failure. Suffering from heart failure results in multiple hospital visits and thus demands a great amount of resources. The future perspectives of treating heart failure include home nursing, remote medicine and remote monitoring. Professor Sinnaeve emphasized the monitoring of water excess. Water excess in the body results in rapid decrease of heart function. Nowadays, this water excess is only observed when patients show several symptoms. Earlier detection would be a great step forward in treatment. A lot of research regarding monitoring water excess is already conducted, however, the rhythm of our HEKcite cells could be influenced by osmolarity which could be a tool for fluid measurement.

Finally, professor Sinnaeve indicated that our project could be useful during phase 1 clinical studies in cardiology as well as other branches of medicine. Currently, real-time monitoring of different drug concentrations is highly requested by medical regulatory agencies. These measurements can give more insight in the mechanism of action of different drugs but can also be used as a control mechanism for patient compliance. During clinical studies, it is of great importance to verify drug intake as this determines the outcome of the study. With our device researchers would be able to continuously monitor drug concentrations. This would help validate new therapies that could otherwise be declined due to lack of patient compliance. Additionally, the HEKcite cells could provide valuable information on a drug’s therapeutic time window. Summarized, our device could result in the acquirement of more detailed information during clinical studies.

Before this meeting, when trying to influence the rhythm of the HEKcite cells, we were exclusively using ivabradine. However, after receiving the valuable information provided by professor Sinnaeve, we decided to adjust our experiments, namely by incorporating ethosuximide, of which professor Van Paesschen reassured us that therapeutic drug monitoring is crucial. Ethosuximide is an anti-epileptic and acts as an inhibitor of T-type calcium channels such as the 𝛼1G channel present in the HEKcite cells. We did, however, not completely discard ivabradine as professor Sinnaeve did mention it could function as a proof-of-concept. By changing these aspects of our research, we attempt to give our project more societal relevance in order to be able to help a wider range of patients.

Professor Filip Bouckaert

Filip Bouckaert is a geriatric psychiatrist and member of the University Psychiatric Center (UPC) at KU Leuven. He is specialised in geriatric psychiatry, anxiety, mood disorders, psychosis and electroconvulsive therapy (ECT).

As psychiatry seemed a very interesting target for therapeutic drug monitoring, we contacted Filip Bouckaert for a second opinion. He suspects that only a small amount of psychiatric patients, people severely affected by bipolar disorder, would benefit from our project. However, he expects that their quality of life would be hugely improved.

During our discussion with Filip Bouckaert, he was very enthusiastic about the project. Additionally, he has provided us with some new ideas and possibilities regarding HEKcite in the field of psychiatry.

First, he mentioned that only a limited number of antipsychotic drugs are available, of which clozapin, depacin, notrilin and lithium-based medicine are the most common examples. As a result of the limited treatment options, side effects are prevalent and often unavoidable. These effects may be severe and even lethal, especially when multiple drugs are taken by a patient. For example, cardiac arrhythmias can occur. Therefore, the psychiatrist suspects that the system developed in our project could provide a peace of mind for these patients, as these arrhythmias may result in sudden death.

When further discussing the possibilities of HEKcite in the field of psychiatry, Filip Bouckaert declared that, despite his enthusiasm for our project, he suspects that only a limited number of psychiatric patients, people suffering from severe bipolar disorder, could benefit from the therapeutic drug monitoring we propose. However, he thinks it would greatly increase their quality of life, specifically as drug compliance is a well-known problem for bipolar patients. During symptomatic episodes, the disease affects the patients’ life severely, and might result in manic episodes, depression, et cetera. However, during asymptomatic periods, the patients often lose the motivation to take the drugs, which results in more frequent relapses. As a result, they may end in a vicious circle of relapse after relapse. Using the HEKcite therapeutic drug monitoring device, a dynamic measurement of the blood levels would be possible. This way, the doctors will notice when an alarming change in the rhythm appears and they can intervene before it is too late. The device can thus work as modern ‘gate keepers’.

Another small group of patients that could be helped with our project are those suffering from aichmophobia, the fear of needles and sharp objects, as fewer blood samplings are needed after the device is implanted.

Filip Bouckaert also noted the importance of monitoring drugs with a small therapeutic window, e.g. lithium-carbonate. When the blood levels of these drugs are too high, the drugs are very toxic for the patients. We suggested that the HEKcite monitoring device could be helpful in monitoring these risk-bearing drugs, especially in the psychiatric world, where patients show mainly subjective clinical symptoms. Currently, doctors look for certain side effects, such as tremor, to determine whether patients have a toxic amount of drugs in the blood. Therefore, measuring the concentration of lithium-carbonate before clinical symptoms as tremor appear, using for example the HEKcite device, could be helpful. However, he suggests that when we look into this application further, we must make sure to take the metabolization of the drugs, and the interindividual differences thereof, into account. This is important as these differences may influence the precision of our device.

Lastly, it is important to consider the fact that some drugs influence other drugs as well. For example: lithium is metabolized by the kidneys, but other therapeutics, such as angiotensine, ACE-inhibitors, NSAIDs and lis-diuretics affect the kidneys. Moreover, the outside temperature and the amount of hydration can also influence the blood levels: The more dehydrated a person is, the higher the drug blood levels are, and vice versa. This could affect the frequency of our device and could give a distorted image of the actual drug level in the body.