Nils Tore Vethe
Head, Clinical Pharmacology, Rikshospitalet
Department of Pharmacology
Oslo University Hospital, Norway
It is exciting to return to our interviews this month and especially with such a great one with Nils Tore Vethe from Oslo. Nils shares about his work as head of the Clinical Pharmacology Section at Rikshospitalet – known for their work in immunosuppressant TDM – where they impressively analyze some 200 IS samples every day, year-round. Nils talks about some unique initiatives including home-based blood sampling and TDM including volumetric finger-prick blood sampling for some tacrolimus treated patients, exploratory pharmacological methods in tissues and cells, and more. Take a look!
Can you tell us a little bit about your respective roles? What is a typical day like for you?
My workplace is at Oslo University Hospital. It is a large hospital with more than 20,000 employees in various sub-hospitals and a number of clinics across. The Department of Pharmacology is part of the Division of Laboratory Medicine and I am head of the Clinical Pharmacology Section at Rikshospitalet. Our activities are largely about TDM, pharmacogenetics and related counseling services. Rikshospitalet is the only Norwegian center that performs organ transplantation, and the laboratory thus has a large volume of immunosuppressive drug TDM. Our strategy states that we should conduct development and research that support our core activities, and this implies that we are increasingly trying to integrate development and innovation in our practice. At the middle management level, I am involved in both detailed professional issues and administrative and strategic tasks. It is interesting to be on this boundary line, but it is also extensive since many cases go through this level. Much of the daily work involves answering inquiries, preparing plans and making assessments. We hold regular meetings to ensure that decisions are thoroughly discussed and anchored, and it is important to ensure that relevant information reaches those concerned. The section is interdisciplinary to ensure broad competence coverage, and it is important to facilitate good discussions and collaboration that will lead us forward.
Is there anything that your laboratory does, or that is done at your centre, that you would consider innovative?
Within clinical pharmacology, the innovation potential often lies in new applications and in the improvement of methods used to personalize drug treatment.
We consider chromatography/mass spectrometry methods to have superior quality for drug analyses, and we work to simplify the associated workflow in order to be able to offer such analytical methods with a short turnaround time. An important theme is to develop automation solutions, and then to streamline and standardize work processes that are complex and that can give rise to variation by manual methods. We have an ongoing project regarding automating the sample preparation in connection with mass spectrometric analysis of protein-based drugs and biomarkers. This is an example where manual sample preparation is a barrier to implementation, and automation will probably create an enabling framework for analyses in practice.
Exploration of pharmacological methods in cells and tissues is something we have been interested in, both to obtain new pharmacological knowledge and to look for new concepts of drug monitoring. There are still technical challenges related to this topic, but it is gradually evolving, and it should have a potential especially for immunosuppressants and cancer drugs.
Our hospital has an overall strategic and innovative program for the development of home-based hospital services. Such services are believed to be an important part of the future hospital, and some are already established. In our laboratory, we perform home-based blood sampling and TDM. Together with promoters at clinical transplantation departments, we have moved into this field and are constantly working to expand it. It has great potential for simplification and quality improvement of the health service, and it is now also highly relevant as a preventive measure against the spread of infection.
What technological innovations have entered into use during your career that have permitted a change, or evolution, in practice?
Although this is not something that has happened overnight, I would say that the introduction of user-friendly and more efficient liquid chromatography mass spectrometry platforms has meant a lot to the quality of TDM. The use of LC-MS/MS requires considerable expertise to ensure reliable utilization, and it needs streamlining to provide gains in terms of efficient workflow in the daily operating situation. In parallel with the availability of good internal standards some years ago, we switched from labor-intensive LC-UV methods to simpler LC-MS/MS methods with respect to the quantification of thiopurines and busulfan. I consider this as a game-changer for our internal workflows and also considerable improvement of the robustness and precision of results.
The transition to LC-MS/MS for immunosuppressant TDM required optimization of our work processes. We are among the largest laboratories in this field where we analyze about 200 samples daily, and it is a complexity due to different degrees of prioritization of the samples. In 2015, we launched our new in-house developed platform for these analyses, then based on robotic sample preparation and two-channel chromatography coupled to MS/MS. After this, our skilled and committed employees have maintained the instrument performance and the release of analysis results Monday to Sunday all year round. I am both proud and impressed that this takes place every day in our laboratory.
Another game-changer is the concept of volumetric finger-prick blood sampling. Combined with reliable analytical methods, this opens up the opportunities for home-based sampling and follow-up via video consultations, which will most likely suit a majority of patients. Such methods must be carefully validated and require interdisciplinary collaboration and thorough patient training to ensure good quality. Today, finger-prick tacrolimus TDM has been implemented in selected kidney transplant recipients. It is a priority for us to further develop.
How did you become interested in your area of expertise?
My master’s degree thesis in pharmacy was about the molecular pharmacodynamics of mycophenolate. I was then involved in translational research, discovered that this was an exciting field to be in, and got further research opportunities through PhD work. I found the relationship between pharmacology, technical development and personalized treatment highly interesting.
Is there anything that you’ve seen or heard about recently and thought “I’d like to incorporate that idea at my center”?
I think that the concept of ex vivo models for drug response predictions are interesting. If I get the opportunity, I would like to contribute to the development of this, since I see it as a possible new application area within personalized drug treatment.
What sort of research do you have on the horizon that you think might influence clinical practice in the future?
I believe that the further development of home-based blood sampling will be important for a part of the future TDM, often in combination with other biomarkers. A rational balance between pharmacogenetic testing and TDM will also be crucial for the best possible drug treatment, and a gradual transition to sequencing technology can create new opportunities. In recent years I have worked with cardiovascular pharmacotherapy and especially research in relation to statin treatment. It has been very interesting to see how perceptions of side effects in the population, and also among professionals, affect the realization of the potential that lies in cholesterol-lowering treatment. Also in this setting we include analyses in tissues and cells to gain more knowledge about mechanisms and biomarkers. The knowledge we provide can help optimize statin treatment in larger patient groups. I think it is important that our services support overall societal and population perspectives along with focusing on the individual patient. I am also fascinated by how some issues about drug efficacy have changed focus from complex genetic explorations to the simple question of whether the patient is taking the drug or not. Adherence to drug therapy is not unexpectedly the most important factor in achieving drug efficacy, and we are currently developing and evaluating clinically applicable methods that can improve statin adherence in coronary heart disease patients.
What do you consider is the future for TDM and CT? What are you excited about? What are the challenges we face?
I believe that the key to long-term success will be to further develop methods that can be used to predict drug effects, including new concepts that go beyond regular blood plasma concentration measurements and single nucleotide variant analyses. Although it is demanding, I think we should make an effort to implement more advanced pharmacological analyses and new molecular biology techniques to a greater extent. Multifactorial models and calculation algorithms will probably gain increased relevance and should be incorporated into user-friendly interfaces. One of the main challenges will be to achieve funding and feasibility for both laboratory infrastructure and clinical studies that are necessary for both exploratory and conclusive studies.
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