Pharmacology of ImmunoSuppressive Drugs and of Transplantation (PIST)
UMR INSERM 850

Contact

Pierre Marquet – Director
(0033) 555 05 60 17

Adress : Centre de Biologie et de Recherche en Santé (CBRS), 2ème étage Rue du Pr. Bernard Descottes 87025 LIMOGES Cedex

Administrative Supervision : Université de Limoges – INSERM

Parent Institute : GEIST

Doctoral School : ED 524 – Bio-Santé

Presentation

The UMR 850 Joint Research Unit carries out translational research on drugs used in transplantation with the aim of optimizing their benefit/risk balance, based on a personalized medicine approach. This research focuses on :
• Identifying pharmacokinetic, pharmacogenetic, pharmacodynamics and environmental factors of (therapeutic and toxic) treatment response variability.
• Setting-up tools for compensating this variability or for the prevention or treatment of adverse events
• Validating the clinical and medico-economic benefit of these personalized medicine tools.

Research themes

• “Pharmacodynamics” axis :
  – Investigation of the pharmacodynamic biomarkers of immunosuppressive drugs (ISD), particularly calcineurin inhibitors (CNI, cyclosporine, tacrolimus) that may help to individualize patient treatments
  – Study of the toxic mechanisms of CNI on vascular endothelium (allograft vasculopathy) and renal tubules (chronic renal allograft dysfunction)
  – Search for early urine biomarkers of kidney graft lesions
• “Pharmacogenomics” axis :
  – Involvement of genetic polymorphisms in the protein targets of ISD (CNI and mTOR inhibitors): o In the variability of cell and clinical responses o In the occurrence of post-transplantation lymphoproliferative diseases (PTLD)
  – Identification of rare exon variants in precocious PTLD through whole-exome sequencing
  – ISD effects on epigenetic marks and epigenetic status effects on ISD response.
• “Pharmacometrics” axis :
  – Molecular modelling of trans-membrane transfers of anti-CMV drugs and ISD
  – Development of pharmacokinetic models and Bayesian estimators for ISD and clinical validation
  – Clinical transfer of these tools through the unit’s expert system “ExpertIS” and website ISBA (https://pharmaco.chu-limoges.fr)
  – Development of models for the prediction of graft and patient outcomes based on multicentric, retrospective and prospective cohort studies
  – Pharmaco-epidemiologic study of transplanted patient adherence, adverse effects, quality of life and their determinants
  – Pharmaco-economic study of different therapeutic strategies in transplantation.
• “Therapeutic innovation” axis :
  Uterus transplantation

Keywords

Pharmacokinetics ; Pharmacogenetics ; Biomarkers ; Toxicity ; Pharmacoepidemiology ; Pharmaco-economy ; Translational Research ; Clinical Research ; Transplantation ; Immunosuppressive Drugs

Honours

Pierre Marquet : “Pippenger Award for outstanding contributions to Therapeutic Drug Monitoring” – International Association of Therapeutic Drug Monitoring and Clinical Toxicology ( 2009 )
Patrick Trouillas : Award of the best foreigner scientist of the Regional Center of Advanced Technologies and Materials – Czech Rep. ( 2014)

Equipment / Technical resources

Mass spectrometry ; Proteomic analysis ; PCR, real-time PCR ; Cell culture ; Molecular biology ; Pharmacokinetic modelling, disease modelling, molecular modelling

Partnerships

Active National University Partnerships : FHU SUPORT with Poitiers (U1082 “Ischemia-Reperfusion in organ transplantation”) and Tours (EA4245 “dendritic cells, immune modulation and transplantation”) ; Vast collaborative network with organ transplantation centres (e.g., 7 renal transplantation centres involved in our EPHEGREN study) ; Pharmacogenetics: Prof. D Anglicheau, U845 INSERM, Hôpital Necker, Paris ; Proteomics and biomarkers: 6 French partners in the FP7 BIOMARGIN programme
Current International University Partnerships : – FP7 BIOMARGIN: Partners in Germany, Belgium, Sweden and The Netherlands ; Pharmacology of ISD: partnerships with Profs. P Wallemacq, V Haufroid & M Mourad, Cliniques Saint-Luc, Belgium ; and Profs. T van Gelder and R van Schaik, Erasme Hospital, The Netherlands ; Pharmacodynamics of ISD: Prof. Patricia Espéron, university of the republic of Uruguay (Ofelia Noceti’s thesis co-direction) ; Prof. Mercedes Brunet, Hospital Clinic of Barcelona, Spain ; PK and PK/PD modelling: M Neally & R Jelliffe, L.A. PK lab, USC, USA ; Disease modelling: N. Holford, Univ. Auckland, New Zealand ; Molecular modelling: Regional Center of Advanced Technologies and Materials (Olomouc, Czech Republic); Institut für Chemie, Technische Universität Berlin (Berlin, Germany); Laboratory for Chemistry of Novel Materials (Mons, Belgium) ; Clinical transfer of personalized medicine tools via the unit’s ISBA website, used by a dozen international transplant units (European, American, Asian and North African)
National Industrial Partnerships : Contracts with Roche Pharma, Novartis, Astellas.
International Industrial Partnerships : Contracts with Hoffman-Laroche Israël, Astellas Germany, Thermo-Electron USA, Shimadzu Germany
Partnerships with National Organizations and Institutions : INSERM ; CHU (University Hospital) of Limoges

Industrial applications

The ABIS/ISBA website on individualized dosing for transplant patients, developed based on the UMR-S850 results, received over 9,000 requests in 2014, from more than 54 transplant units, including a dozen foreign units (Europe, North America, South America and North Africa). The site’s activity in France is financed through inter-hospital invoicing. (https://pharmaco. chu-limoges.fr)