NCT04526431

Tacrolimus Pharmacokinetic Subpopulations

Tacrolimus Pharmacokinetic Subpopulations: Prospective Mechanistic Investigations of the Tacrolimus C/D Ratio

• Status: Recruiting
• Phase: —
• Study type: Observational
• Enrollment: 180 (estimated)
• Sponsor: University Hospital, Grenoble · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This prospective study will investigate the concentrations of tacrolimus metabolites (M-I and M-III) over the four first years post-transplantation. A differential metabolism might result in different metabolites' concentration and explain a kidney survival difference between "high rate metabolism" (defined as a concentration/dose ratio, C/D ratio, lower than 1.04 µg/l/mg) and other patients. The primary endpoint is therefore to compare tacrolimus metabolites' concentrations with respect to the group, either \< or \>= 1.04 µg/l/mg, in order to detect differences in tacrolimus metabolization between these groups.

Detailed description

Tacrolimus is the cornerstone of immunosuppression in renal transplantation, but its nephrotoxicity, in particular, makes it a drug with a narrow therapeutic range, requiring regular pharmacokinetic monitoring. Several studies have demonstrated a relationship between concentration (residual tacrolimus) and dose (prescribed daily tacrolimus) ratio, or C/D ratio, and graft survival. "Fast metabolizers" have been identified by a C/D ratio of less than 1.05 and have poorer graft survival than other renal transplant recipients. The determinants of the C/D ratio (the clinical or biological factors influencing the C/D ratio) are not known. The purpose of the TIPS study is to prospectively identify tacrolimus metabolism patterns, based on the C/D ratio, and to identify the determinants of the C/D ratio. The investigators assumed that different metabolism profiles are associated with different degradation profiles of tacrolimus. These degradation profiles can be identified by analysis of known plasma metabolites of tacrolimus (M-I and M-III) and by pharmacogenetic analysis of genes involved in the metabolism of tacrolimus. Also, since the pharmacokinetic profile can be associated with the therapeutic strategy (prolonged-release vs. immediate-release tacrolimus form), it will be investigated in the study in parallel. The hypothesis of this work is that the pharmacokinetic parameters of tacrolimus and its metabolites are associated with renal transplant survival and simultaneously with the therapeutic strategy of the drug. The investigators hope that this will explain the relationship between the C/D ratio of tacrolimus and graft survival, in order to tailor tacrolimus treatment to individual patients (adaptation of the therapeutic strategy, choice of optimal dose). For this prospective tri-centric randomized prospective study, new renal transplant patients who are scheduled to receive immunosuppression including tacrolimus will be included and randomized between two therapeutic strategies (prolonged-release vs. immediate-release tacrolimus form) within 7 days after transplantation. Patients will be followed for 4 years. Regular consultations will be provided (W6, M3, M6, M12, M24, M36 and M48) including usual biological analyses for renal transplant follow-up, full prescriptions and adherence questionnaire (BAASIS) but also a systematic biopsy of the renal transplant (M3 and M12) and an abbreviated pharmacokinetic study of tacrolimus exposure (M3).

Conditions

• Kidney Transplant Failure and Rejection
• Immunosuppression-related Infectious Disease

Interventions

Type	Name	Description
DRUG	Dosage Forms Oral	Dosage form of tacrolimus (extended release tacrolimus or immediate release tacrolimus)

Timeline

• Start date: 2020-07-28
• Primary completion: 2026-08-01
• Completion: 2027-08-01
• First posted: 2020-08-25
• Last updated: 2021-02-10

Locations

2 sites across 1 country: France