IPPRITT – Individual Profiling and Prevention of Risks with Immunosuppressive Therapies and Transplantation
UMR Inserm-CHU 1248

The UMR 1248 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:

• Biomarker 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 renal tubules (chronic renal allograft dysfunction) – Search for early urine biomarkers of kidney graft lesions – Biomarkers in liver transplantation
• Pharmacogenomics axis : Involvement of rare exon variants in extreme phenotypes in transplantation by 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 ; Translational Research ; Clinical Research ; Transplantation ; Immunosuppressive Drugs

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

Fields of application : Health, pharmacy, bio-industry (phamacology, organ transplantation) Industrial applications: The ABIS/ISBA website on individualized dosing for transplant patients, developed based on the UMR 1248 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). In 2019, this activity and another telemonitoring application issued from the unit’s works will be transferred to the unit’s spin-off company Optim’Care Chair of Excellence: Pharmacologie de la Transplantation Cluster: EuroBioMed

• National University Partnerships: 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
• 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: Clinical research contracts with Sandoz, Astellas and Chies
• International Industrial Partnerships: Partnerships with Mosaïques Diagnostics (Germany) et AcureOmics (Sweden) and Sandoz Europe (Germany)