Tacrolimus Pharmacokinetic Subpopulations

Kidney Transplant Failure and Rejection Clinical Trial

— TIPS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04526431
• Other study ID #: TIPS
• Status: Recruiting
• Start date: July 28, 2020
• Est. completion date: August 1, 2027

Study information

• Verified date: February 2021
• Source: University Hospital, Grenoble
• Contact: Thomas JOUVE, MD, PhD
• Phone: +33476765460
• Email: tjouve[@]chu-grenoble.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: August 1, 2027
• Est. primary completion date: August 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Kidney transplant patients at the CHUGA, CHU Saint-Etienne or CHU Clermont-Ferrand, whose new transplant is no more than 7 days old (inclusive)

• Patients initially treated with tacrolimus as an immunosuppressant, combined with mycophenolate (MMF), mycophenolic acid (MPA) or everolimus (EVR), with or without corticotherapy.

• No plans to remove tacrolimus from the patient's immunosuppressive treatment (e.g. no plans to switch to belatacept a priori), during the first 4 years post-transplantation.

• Affiliation to or beneficiary of a social security scheme

• Able to read and understand the terms of the protocol

• Informed consent obtained, including specific consent for genetic analysis of target genes.

• For women of childbearing potential, presence of effective contraception (already acquired for patients treated with mycophenolic acid as an immunosuppressant).

Exclusion Criteria:

• Contraindication to the use of tacrolimus

• Patient already treated with tacrolimus at the time of transplantation

• Pregnant, parturient or breastfeeding women

• Patient deprived of liberty by judicial or administrative decision

• Patient under guardianship or curatorship, or receiving forced psychiatric care

• Person admitted to a health or social institution

• Subject cannot be contacted in case of emergency

• Subject in period of exclusion from another study

Related Conditions & MeSH terms

• Communicable Diseases
• Immunosuppression-related Infectious Disease
• Infection
• Kidney Transplant Failure and Rejection

Intervention

Drug:
• Dosage Forms Oral
Dosage form of tacrolimus (extended release tacrolimus or immediate release tacrolimus)

Locations

Country	Name	City	State
France	Grenoble University Hospital	Grenoble	Rhone Alpes
France	Saint Etienne University Hospital	Saint-Étienne	Rhone Alpes

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Grenoble	Chiesi SA/NV

Country where clinical trial is conducted

France, 

References & Publications (4)

Egeland EJ, Robertsen I, Hermann M, Midtvedt K, Størset E, Gustavsen MT, Reisæter AV, Klaasen R, Bergan S, Holdaas H, Hartmann A, Åsberg A. High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation. Transplantation. 2017 Aug;101(8):e273-e279. doi: 10.1097/TP.0000000000001796. — View Citation

Jouve T, Fonrose X, Noble J, Janbon B, Fiard G, Malvezzi P, Stanke-Labesque F, Rostaing L. The TOMATO Study (Tacrolimus Metabolization in Kidney Transplantation): Impact of the Concentration-Dose Ratio on Death-censored Graft Survival. Transplantation. 2020 Jun;104(6):1263-1271. doi: 10.1097/TP.0000000000002920. — View Citation

Jouve T, Noble J, Rostaing L, Malvezzi P. An update on the safety of tacrolimus in kidney transplant recipients, with a focus on tacrolimus minimization. Expert Opin Drug Saf. 2019 Apr;18(4):285-294. doi: 10.1080/14740338.2019.1599858. Epub 2019 Apr 1. Review. — View Citation

Thölking G, Fortmann C, Koch R, Gerth HU, Pabst D, Pavenstädt H, Kabar I, Hüsing A, Wolters H, Reuter S, Suwelack B. The tacrolimus metabolism rate influences renal function after kidney transplantation. PLoS One. 2014 Oct 23;9(10):e111128. doi: 10.1371/journal.pone.0111128. eCollection 2014. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Tacrolimus metabolite concentration	The concentration of tacrolimus metabolites M-I and M-III will be evaluated by liquid chromatography / tandem mass spectrometry (LC-MS/MS) given in micrograms per litre (µg/l).	month 3
Primary	Genotyping	Genotypes of target genes involved in tacrolimus metabolism (CYP450 3A5, CYP450 3A4, ABCB1)	Enrollment
Primary	Tacrolimus residual concentration	In addition to the Tacrolimus residual concentration assessed at each visit, this measure will also be performed at T0, T+1h and T+3h for immediate-release tacrolimus and T0, T+1h and T+8h for prolonged-release tacrolimus after treatment. The measurement at T+8h will be carried out on blotting paper with a drop of capillary blood which will be returned by mail, using an envelope given to the patient during the visit. These three measuring points will be used to identify the abbreviated kinetics of tacrolimus during M3 visit.	month 3