Tacrolimus Pharmacokinetic Subpopulations

NCT04526431 | Recruiting

• 1 other identifier: TIPS
• Study Type: observational
• Target: 180
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Kidney Transplant Failure and Rejection; Immunosuppression-related Infectious Disease

Keywords

Kidney transplantation; Pharmacokinetic; Tacrolimus; Concentration-dose ratio; Pharmacogenetic

Outcome Measures

Primary Outcomes (3)

• 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

• Genotyping

  Genotypes of target genes involved in tacrolimus metabolism (CYP450 3A5, CYP450 3A4, ABCB1)

  Enrollment

• 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

Study Arms (2)

Tacrolimus once-daily

Patients receiving tacrolimus as a once-daily formulation (Envarsus)

Drug: Dosage Forms Oral

Tacrolimus bid

Patients receiving tacrolimus as a twice-a-day formulation.

Drug: Dosage Forms Oral

Interventions

Dosage Forms Oral DRUG

Dosage form of tacrolimus (extended release tacrolimus or immediate release tacrolimus)

Tacrolimus bid; Tacrolimus once-daily

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

The study population is made of kidney transplant patients with living or deceased donors at Grenoble University Hospital, Saint Etienne University Hospital or Clermont-Ferrand University Hospital.

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Grenoble: lead
• Chiesi SA/NV: collaborator

Study Sites (2)

Grenoble University Hospital

Grenoble, Auvergne-Rhône-Alpes, 38043, France

RECRUITING

Saint Etienne University Hospital

Saint-Etienne, Auvergne-Rhône-Alpes, 42000, France

NOT YET RECRUITING

Related Publications (4)

• 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.

  PMID: 31415035 BACKGROUND

• 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.

  PMID: 30909754 BACKGROUND

• Tholking G, Fortmann C, Koch R, Gerth HU, Pabst D, Pavenstadt H, Kabar I, Husing 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.

  PMID: 25340655 BACKGROUND

• Egeland EJ, Robertsen I, Hermann M, Midtvedt K, Storset E, Gustavsen MT, Reisaeter AV, Klaasen R, Bergan S, Holdaas H, Hartmann A, Asberg 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.

  PMID: 28452920 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

The main result of the TIPS study will be longitudinal trough concentrations of tacrolimus metabolites, over the four first years post-transplantation. In order to explain the tacrolimus C/D ratio differences, confounding factors will also be investigated, such as CYP3A4, CYP3A4 and ABCB1 genotypes. DNA will therefore be sampled on the day of inclusion.

MeSH Terms

Conditions

Rejection, Psychology

Interventions

Dosage Forms

Condition Hierarchy (Ancestors)

Social Behavior; Behavior

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations; Technology, Pharmaceutical; Investigative Techniques

Study Officials

• Thomas JOUVE, MD, PhD

  University Hospital, Grenoble

  PRINCIPAL INVESTIGATOR

• Lionel ROSTAING, MD, PhD

  University Hospital, Grenoble

  STUDY CHAIR

Central Study Contacts

Thomas JOUVE, MD, PhD

CONTACT

+33476765460; tjouve@chu-grenoble.fr

Johan NOBLE, MD

CONTACT

+33476765460; jnoble@chu-grenoble.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2020
• First Posted: August 25, 2020
• Study Start: July 28, 2020
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2027
• Last Updated: February 10, 2021

Record last verified: 2021-02

Locations

FR (2)