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

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.

Sex

All

Minimum age

18 Years

Maximum age

70 Years

Inclusion Criteria:

Healthy volunteers:

* Age: 18 to 70 years.
* Ethnicity: Hispanic, African American.
* Gender: male and female.
* Condition: healthy.
* Informed consent: granted and signed informed consent at the time of inclusion and agreement to comply with all the procedures included in the protocol.

Waiting List Patients:

* Age: 18 to 70 years.
* Ethnicity: Hispanic, African American.
* Gender: male and female.
* Being active on the waiting list for liver transplantation
* Informed consent: granted and signed at the time of inclusion and agreement to comply with all the procedures included in the protocol.

Transplant Patients:

* Age: 18 to 70 years.
* Ethnicity: Hispanic, African American.
* Gender: male and female.
* Drug therapy: cyclosporine or tacrolimus, with or without mycophenolic acid derivatives and/or corticosteroids.
* Informed consent: granted and signed at the time of inclusion and agreement to comply with all the procedures included in the protocol.

Exclusion Criteria:

Healthy volunteers:

* pregnancy
* breastfeeding
* chronic drug treatment
* non healthy

Waiting List Patients:

* Patients with previous transplant.
* Patients with more of one transplanted organ.
* Patients on anticalcineurin drugs.
* Patients with impaired renal function - creatinine clearance ≤ 20 ml/min.

Transplant Patients:

* Pregnant or breastfeeding.
* Patients with prior retransplantation.
* Patients with more of one transplanted organ.
* Patients with impaired renal function - creatinine clearance ≤ 20 ml/min.
* Everolimus indication at any time during treatment.

• DERIVEDNoceti O, Pouche L, Esperon P, Lens D, Vital M, Tourino C, Gerona S, Woillard JB, Marquet P. Activity of the Calcineurin Pathway in Patients on the Liver Transplantation Waiting List: Factors of Variability and Response to Tacrolimus Inhibition. Clin Chem. 2017 Nov;63(11):1734-1744. doi: 10.1373/clinchem.2017.272534. PMID 29054923