Study of PD/PK/PG Relationships of Tacrolimus and Cyclosporin in Liver Transplant Patients

Summary

To search for suitable pharmacodynamic biomarkers, i.e., with high specificity for calcineurin inhibition and most affected by inter-individual variability, our works aimed at exploring the pharmacodynamics of CNI, the strength and variability of signal translation along the calcineurin pathway, as well as the steps where sources of internal (genetic) or external variability are the most influential.

In order to achieve this, we assessed simultaneously NFAT1 translocation into the nucleus of peripheral blood mononuclear cells (PBMC) (NFTA1 being the main NAFT isoform in resting and activated lymphocytes), the intracellular expression of IL-2 in CD3+, CD4+ and CD8+ T cell subsets and the membrane expression of CD25 (IL-2Rα), a surface marker of T cells activation, in T cells at large. A non-interventional clinical trial was set up in healthy volunteers, patients registered on a liver transplantation waiting list (WLP) and liver transplant recipients (LTR). A different question was addressed in each group: The healthy volunteer study (n=35): explored TAC PD along the calcineurin pathway by exposing PBMC ex-vivo; modelled signal translation along this cascade; examined the interindividual variability of TAC PD parameters; and investigated the sources of the variability observed and their contribution at each step of the calcineurin pathway. Furthermore, it allowed us to evaluate the analytical variability of our techniques as well as the intra-individual variability of TAC PD parameters. WLP (n=19) were enrolled to confirm in patients with liver diseases the results obtained in healthy volunteers, as well as to test the potential influence of their initial disease on the ex-vivo pharmacodynamics of TAC. The aims of the transversal study of LTR on CNI (n=80) were to further explore the interindividual variability in the PD of CNI in realistic clinical conditions, i.e. in situations of residual PD activities under tacrolimus or cyclosporine exposure, and the potential pharmacogenetic (PG) sources of such variability. The (still small) group of liver transplant patients (n=9) enrolled immediately before transplantation and followed-up with serial monitoring along the first year post-transplantation was intended to explore the relationships between CNI PD and clinical responses.

Conditions

• End Stage Liver Disease
• Rejection
• Infection
• Malignancy
• Toxicity
• Diabetes

Sponsors & Collaborators

• INSERM UMR-S850, Limoges, France

  collaborator UNKNOWN

• University Hospital, Limoges

  collaborator OTHER

• PEDECIBA, Uruguay

  collaborator UNKNOWN

• Universidad de la Republica

  collaborator OTHER

• ANII (Agencia Nacional de Investigación e Innovación), Uruguay

  collaborator UNKNOWN

• Scientific Cooperation Service, French Embassy, Uruguay

  collaborator UNKNOWN

• Hospital Central de las Fuerzas Armadas, Uruguay

  collaborator UNKNOWN

• ECOS Sud Program France-Uruguay

  collaborator UNKNOWN

• National Center for Liver Transplantation, Uruguay

  collaborator UNKNOWN

• UDA Centro Nacional Hepato-Bilio-Pancreático

  lead OTHER

Principal Investigators

• Ofelia M Noceti, PhD, PharmD · National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas

• Solange Gerona, MD · National Center for Liver Transplantation and Liver Diseases Department, Hospital Central de las Fuerzas Armadas

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2011-05-01

Primary Completion

2015-02-28

Completion

2021-05-17

Countries

• Uruguay

Study Locations