This month I had the privilege to interview the director of my doctoral thesis, Professor Pierre Marquet (Limoges, France). I thought I knew the department and research laboratory, and their respective histories, quite well. I was delighted to learn a lot more from the interview, a testament to the extraordinary and diverse work achieved by Pr. Marquet, spanning several decades.
Can you tell us a little bit about yourself and your respective professional roles?
I’m head of the Department of Pharmacology, Toxicology and Pharmacovigilance at Limoges University Hospital and Director of the research team “Pharmacology of Immunosuppressants and Transplantation” at the University of Limoges. Since last October, both labs are now located on the same level of a new building that these two institutions have built together in order to facilitate translational research. It really helps me to be able to go from one lab to the other several times a day, so much so that I chose to have one office. I’m also involved in numerous directorial roles: vice-president of the hospital board of directors in charge of research (since 2007); director of the core facility of mass spectrometry and NMR at Limoges University; member of the scientific council of Limoges University; member of an evaluation committee (“Health technologies, pharmacology and toxicology”) at the French Institute of Health and Medical Research, INSERM; evaluator of INSERM-certified research teams; coordinator of a European Research Program on BIOmarkers of Renal Graft INjuries (BIOMARGIN); and member of editorial and association boards, including IATDMCT, of course.
Dario Cattaneo once described the lab in the pharmacology department in Limoges as making him feel like a child in a candy shop (Compass March 2011). Can you tell us some of the technologies, work-flows, tools etc. that make this department unique in France and internationally? Is there anything that your laboratory does or that is done at your hospital that you would consider innovative in terms of TDM and Clinical Toxicology?
Dario is too kind; I don’t think our department is unique. He visited us a few years ago and we had a great time!
When I first arrived in the department in 1986, as a medical student, there were two GC-MS instruments from an excellent French brand, Nermag®, that no longer operates. In the years that followed, several other GC-MS instruments populated the lab. In 1995, we bought our first LC-MS instrument, a Sciex API100. Together with a PhD student and a lab technician, we developed and published many LC-MS techniques for drugs or toxicants.
We also decided to explore the possibility of setting-up a general unknown screening procedure, similar to the one we used to run on our GC-MS systems. We were lucky enough to start collaborating with Sciex headquarters near Toronto, Canada, where I was invited several times. In 2002, we bought an API2000 QTRAP, the first model of hybrid triple quadrupole – linear ion trap instrument. Our hospital lab is now equipped with 10 LC-MS/MS, several GC-MS and HPLC systems, as well as ICP-AES and ICP-MS instruments for metals and elements, not counting automated immunoassay systems of course.
More importantly, we have a very skilled and well-trained staff of 5 lab engineers (which would be called lab scientists in other countries) and 24 lab technicians to develop new analytical methods, validate them and run them routinely. Our lab is organized in different units: PK & TDM, clinical & forensic toxicology, environmental & occupational toxicology, pharmacogenetics and clinical research. These units are managed by 8 PharmDs or MDs. The other part of the department is the regional Pharmacovigilance center (with a pharmacoepidemiological research activity). We train an average of 10 residents and 10 pharmacy students at any one time.
The rather important size and equipment of our lab, at least by French standards, is due to its continuous growth and diversification over the past 30+ years, under the successive management of Prof. Georges Nicot, Prof. Gérard Lachâtre and since 2011, myself. Forensic toxicology in particular has been a strong incentive to develop new methods to cover an increasingly large range of molecules of pharmacological or toxicological interest and this represents an important activity, with requests coming from several different parts of France. Also, around 30 years ago Prof. Gérard Lachâtre accepted to perform several pesticide analyses in fruits to help a local fruit producer: this turned by chance into a long-lasting and ever growing service to one of the food industry leaders in France. In the meantime, the continuing expansion of our catalog had attracted two or three of the biggest medical laboratories in France, which outsourced specialized analyses in pharmacology-toxicology to our laboratory.
Recently we have been struggling to update our many techniques to make them more automated and with a shorter turn-around time, largely due to the successive retirement of several excellent technicians. I’m concerned that our catalog of tests, which is our driving force, has not been enriched over recent years.
ABIS and PKJust, internet based dose adaptation tools, are well known internationally. Could you tell us the story of how the idea came about, some of the challenges and some things you have learned in setting up the system.
April this year was the 10th anniversary of the internet version of ABIS/ISBA (which stands for ImmunoSuppressant Bayesian dose Adjustment). In 1996 we organised our first pharmacokinetic clinical trial so that our coworker, Dr Jean Debord, could develop PK models and Bayesian estimators for cyclosporine and mycophenolate. We published our first papers in 2000 and a couple of years later organized randomized controlled trial to evaluate the usefulness of mycophenolate mofetil TDM. For this, I distributed diskettes (!) with the Bayesian estimators needed to assess mycophenolic acid AUC to the 11 renal transplantation centers involved in our clinical trial. Then I realized that a few of our colleagues were using these estimators, made with and for adult kidney transplant recipients, in pediatric patients or in heart transplant recipients, for instance, and at odds with the clinical trial regulations. It really scared me and I decided to set up a website where we would be able to update regularly the estimators, propose new ones and hopefully regulate their use somewhat better. We have received more than 70,000 requests over these 10 years, with an average 9,000 per year.
Recent statistics are available in our current ISBA Newsletter:
PKJust is more recent and is the ISBA equivalent for antibiotics and a few other drugs, such as methotrexate. We launched it for use at our hospital to replace our old Abbott software and we found that others were also interested, at least in France.
You are also the head of a research department focusing on the pharmacology of IS. What are some findings that have arisen from this group that have influenced clinical practice? Any current projects that you are excited might influence clinical practice in the future?
Our research unit jointly appointed by INSERM (the French Institute of Health and Medical Research), University of Limoges and Limoges University Hospital is developing a translational research project aiming at optimizing treatments in organ transplantation and immunosuppressive drugs (ISD) in auto-immune diseases. We work in three axes: pharmacometrics, pharmacogenomics and pharmacodynamics. Pharmacometrics began with PK modeling almost 20 years ago and now also includes molecular modeling (in silico models of membrane crossing by drugs), disease modeling (dynamic models of graft survival) and, of course, PK modeling. Pharmacogenomics includes the pharmacogenetics of ISD metabolic enzymes, membrane transporters and target proteins and pathways, whole exome sequencing of particularly rare or severe cases of complications to discover rare mutations with high penetrance, and the role of epigenetics in drug response. Finally, pharmacodynamics encompasses the search of pharmacodynamics and pathophysiological biomarkers and the mechanisms of ISD toxic effects. My colleagues in charge of these different projects, several of whom are IATDMCT members, include: Annick Rousseau, Aurélie Prémaud, Marie Essig, Véronique Loustaud, Caroline Monchaud, Nicolas Picard, Franck Saint-Marcoux, Jean-Michel Achard, Jean-Baptiste Woillard, Patrick Trouillas, Tristan Gauthier, and others.
It’s a long road for research results to reach the clinics. Still, I think our PK models and estimators are being used routinely, as mentioned . I hope some of our pharmacogenetic results can also be used by clinicians, such as the deleterious influence of a Pgp haplotype on the nephrotoxicity of calcineurin inhibitors, or, potentially, urine peptide biomarkers that have been determined from our BIOMARGIN European research program.
Is there anything that you’ve seen elsewhere or heard about and thought “I’d like to incorporate that idea at my center”?
There are indeed many. To cite only a few in TDM and CT: dried blood spot testing (we already made attempts but did not get very far due to a lack of time for development), TDM of monoclonal antibodies and recombinant proteins, or TDM of more antibiotics and antivirals. We aim to work on these as soon as we will have consolidated our transition to faster analytical methodologies.
What do you consider is the future for TDM and CT?
Biomarkers. First, this is all about personalized medicine, and TDM has pioneered personalized medicine. Secondly, proteomics and metabolomics at least require (or can be analyzed using) mass spectrometry, and clinical pharmacologists and toxicologists have mastered this technique for decades. Finally, several groups participating to IATDMCT activities are now involved in biomarker research and this should help to foster this field.
Why is TDM not applied more widely, and what can we do about it?
The main culprit has been the pharmaceutical industry, which has tried to sell “easy solutions” to the prescribers and has despised the idea of lab tests to better use their products. At least, this was the case until they had to invent the concepts of “targeted therapies” and “companion diagnostics” to better sell expensive drugs “only” efficacious in subgroups of patients. If you want to know more about my ideas in this domain, you can read a recent consensus paper (Marquet et al, Therapie. 2015 Jan-Feb;70(1):11-9).
This is also in part our fault as we have not made the necessary efforts to try and demonstrate the usefulness of TDM, by setting up randomized control trials. When we have, we did not impose the best exposure (PK) biomarkers or analytical methods, thus jeopardizing the results of such studies. Why on Earth perform TDM using any available technique or any sampling time just because it’s the easiest? If we can demonstrate its usefulness, we can ask clinicians and nurses (or phlebotomists) their efforts in return.
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