Clinical and Experimental Pharmacokinetics
Policlinico San Matteo, Pavia, Italy
This month we hear form Mariadelfina Molinaro from Pavia, Italy, as we look forward toward our annual congress that will be in Rome this year. Mariadelfina has had a fascinating career spanning several decades, including witnessing developments in analytical chemistry to contribute to the care of AIDs patients in times when the aetiology was being elucidated. She covers numerous historical developments and highlights that while we have come a long way, it is important to reconsider our certainties and be flexible in a context where every field of scientific research is evolving rapidly.
I feel like I say this often recently, but I will say it again: this is one of my favourite interviews and I encourage you all to take a look.
Can you tell us a little bit about your respective roles? What is a typical day like for you?
I am a biologist, and I work as a clinical pharmacologist at the San Matteo University Hospital in Pavia, Italy, where I graduated and obtained two post-graduate specializations, first in Clinical Pathology and later in Applied Pharmacology. Since 2013 I am the head of the Laboratory of Clinical and Experimental Pharmacokinetics of the Department of Diagnostic Medicine, working together with other specialized units.
A typical working day is usually spent in the lab, working both on the classic work of analytical preparation and on the subsequent clinical validation of the exams provided by my unit. We manage about 25,000 tests per year, of which a substantial part is constituted by immunosuppressants, antibiotics and, most recently, also by a considerable increase of antifungal drugs.
I have also been participating as a clinical pharmacologist in a multidisciplinary group of physicians for some years. This group is constituted by physicians from different departments (mainly intensive care, infectious diseases, thoracic transplantation), and meets every 15 days to discuss the significant clinical cases of transplanted patients or those on the waiting list, in order to optimize drug therapy in complex clinical scenarios.
For about two years I have also been collaborating with the clinical toxicology laboratory for second-level analyses and toxicological confirmation providing on-call support.
Is there anything that your laboratory does, or that is done at your hospital/centre, that you would consider innovative?
The mission of San Matteo University Hospital is to pursue scientific research, mainly clinical and translational, in the biomedical field together with hospitalization and highly specialized care services according to standards of excellence. My hospital has two disciplinary specializations: transplantology and internal diseases with high biomedical and technological complexity. It is obvious that the strong vocation for the integration of scientific research is implemented not only in the care sector but also in teaching and laboratories, in a context of functional and/or structural coordination. This continuous and progressive mixing of hybrid activity between research and clinical diagnostics is certainly the predominant part of the activity in my laboratory. In fact, there is a continuous integration of new methods useful for the TDM of new drugs to be applied first within research protocols, which will later be integrated into diagnostics. An example is the quantitative determination in mass spectrometry of new antibiotics (glycopeptides, lipopeptides or β-lactams principally utilized in treating MRSA infections) and immunosuppressants (mainly tacrolimus) even in unconventional matrices, such as heart valves and cellular fractions.
What technological innovations have entered into use during your career that have permitted a change, or evolution, in practice?
Definitely the main breakthrough innovation was the transfer of the large part of the analytical methods to mass spectrometry, while maintaining enzyme immunoassay methods for the daily monitoring and urgent cases involving ‘classical drugs.’ I think that today in Italy, and not only there, mass spectrometry has entered the diagnostic and clinical practice as a method no longer considered as the Cinderella of methods, only for use in academia but recognized as a standard method, even in medium and small laboratories.
This has allowed us not only to significantly increase the panel of analytes on which we are applying therapeutic monitoring, but we have also managed to raise awareness in clinicians at our hospital about the great usefulness of TDM truly personalized therapy.
I am aware that there is still a long way to go, because very often doctors are so busy in the management of patients that sometimes the result of the TDM evaluated as “in or out of range”, while, instead, it is the result of infinite series of variables that we often do not know (dose, mode of administration, concomitant drugs, underlying disease…). But it should become our responsibility to do our best to implement a true TDM stewardship within our hospitals.
How did you become interested in area of expertise?
After my master degree in Biological Sciences in 1987, I immediately started attending the Department of Pharmacology at San Matteo Hospital in Pavia, at that time directed by prof. Renato Rondanelli, who is considered one of the founding fathers of Pharmacology in Italy. I joined the Therapeutic Monitoring Lab lead by Dr. Mario Regazzi who, over the course of time, became my teacher and mentor. Those were the dark times of the exponential growth of that new infectious pathology called AIDS and all efforts were aimed at understanding the aetiology and subsequently the care. At that time my scientific curiosity was mainly focused on the plasma quantification of antiviral drugs as a support to the pandemic that was taking place in the world (and that sometimes comes back …).
After a short time, however, I was asked to focus more on immunosuppressants, which at that time were mainly cyclosporine and tacrolimus. I was completely fascinated and absorbed by this new aspect of pharmacology, so that it became the main subject of both my two subsequent post-graduate specializations. Still today I am so much involved in the clinical/pharmacological management of transplant patients that I have become an integral part of a multidisciplinary team that deals with all the clinical problems related to them.
As regards my ‘hat’ as a toxicologist …. well, let’s say that it does not fit well on my head and it fits me tight.
Is there anything that you’ve seen or heard about recently and thought “I’d like to incorporate that idea at my centre”?
I have many ideas, but—as always happens—it is easier said than done. Often, we clash with organizational and budgetary challenges.
In addition to a real need for technological renewal especially on the side of mass spectrometry, I do not deny that I would very much like to be able to combine our knowledge of PK/PD with the pharmacogenetic evaluation of at least the main polymorphisms underlying the variability of some classes of drugs and which are not currently included in the diagnostic panel of my Department.
To be fair, some of them are already part of specific research projects but not yet used as a diagnostic evaluation. This will be one of the next steps to be implemented as soon as possible.
What sort of research do you have on the horizon that you think might influence clinical practice in the future?
I feel lucky to be part of an enthusiastic group of professionals who have also become very close friends over time and who have proved to be a source of ideas about methods to improve patients’ care.
We have already come a long way, but I am sure that many improvements can still be made to truly personalize therapy, keeping in mind that more and more often we deal with combination therapies including immunosuppressive drugs, antimicrobials, antifungals, antivirals, and so on.
Several teams within the IATDMCT are currently working on different sides in order to develop new drug monitoring approaches to achieve the goal of a better quality of life of patients. To do this we also have some different translational clinical trials underway to provide answer to some research questions. The first study refers to the PK/PG evaluation of tacrolimus in heart transplant patients, carried out in different matrices (whole bloods, PBMCs, endomyocardial biopsies) and with a follow-up of 12 months. The second refers to the PK evaluation of daptomycin in plasma and heart valves of patients undergoing valve replacement. Finally, we are carrying out a retrospective study on hydroxychloroquine administered in unconventional doses to Sars-Cov2 positive patients, before the banning on this drug by some regulatory agencies.
What do you consider is the future for TDM and CT? What are you excited about? What are the challenges we face?
In my opinion it is appropriate to reconsider what we believe to be our certainties, because every field of scientific research is evolving so rapidly that what we thought we had learned is already the past. And we must be ready to adapt to these changes, never assume that we have finally understood everything there is to know about a given topic.
Even the patients themselves are increasingly informed about the therapies they are subjected to and are no longer satisfied with knowing the bare minimum on what the doctor decides is best for them.
All these changes in the way we approach the problems, are the basis of the great challenges we face and that we are ready to address them.
How has COVID-19 affected your professional life?
It was a very hard period for everyone, so hard that it is still very difficult for me to express my feelings… and I still wonder ‘when will it really be over?’
As an event with a high emotional impact that affects the community in unprecedented ways, it can generate typical stress reactions, and this stress I have felt much more in my daily life than in the workplace.
Being a hospital manager, my work in the laboratory has not undergone any changes, as it has happened for other colleagues who were diverted to other functions during the months between February and June 2020. By contrast, the most difficult moment of the day was returning home in the evening, when it seemed that the only topic of conversation was the COVID pandemic.
The content of the IATDMCT Blog does not necessarily have the endorsement of the Association.