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Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells (DIFF-TAC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03654794
Recruitment Status : Completed
First Posted : August 31, 2018
Last Update Posted : September 3, 2018
Sponsor:
Information provided by (Responsible Party):
Rennes University Hospital

Brief Summary:

Pharmacokinetics of tacrolimus are highly variable and may result in graft rejection (underdosing) or toxicity (overdosing).

The risk of transplant rejection and the toxicity of tacrolimus can be reduced by pharmacological therapeutic monitoring of the molecule, based on the measurement of residual blood concentrations. Nevertheless, some patients are victims of rejections or toxic signs even though their blood concentrations are in the therapeutic target.

The aim of the study is to describe the pharmacokinetics of tacrolimus diffusion in mononuclear cells as well as the kinetics of effect of the drug on its target protein


Condition or disease Intervention/treatment
Hemochromatosis Biological: Cell pharmacokinetics of tacrolimus

Detailed Description:

Factors responsible for pharmacokinetic variability of tacrolimus are multiple: compliance, diet, drug interactions and also genetic polymorphism of cytochrome P450 3A5 (CYP 3A5) and efflux protein ABCB1 (P-glycoprotein, P-gp).

The mechanism of action of tacrolimus is based on inhibition of calcineurin in T cells. Therefore, tacrolimus intra-lymphocyte concentration may be a finer marker of the risk of transplant rejection or toxicity. The degree of inhibition of calcineurin in the T lymphocyte could also be a pharmacodynamic marker more relevant than the blood concentration. The hypothesis that the ABCB1 efflux pump is the main factor limiting the diffusion of tacrolimus into mononuclear cells is advanced.

The diffusion of tacrolimus into mononuclear cells and the impact of the ABCB1 efflux pump on this diffusion have not been studied to date. The effect kinetics of the drug on calcineurin in mononuclear cells is also unknown.

The aim of the study is to describe the pharmacokinetics of tacrolimus diffusion in mononuclear cells as well as the kinetics of effect of the drug on its target protein: calcineurin in the presence or absence of an efflux pump inhibitor ABCB1 at room temperature and at 4 ° C (in order to inhibit all transport proteins) from blood obtained from 18 patients undergoing bleeding as part of maintenance treatment for hemochromatosis.


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Study Type : Observational
Actual Enrollment : 26 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells
Actual Study Start Date : October 24, 2013
Actual Primary Completion Date : July 6, 2017
Actual Study Completion Date : July 6, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemochromatosis
Drug Information available for: Tacrolimus

Group/Cohort Intervention/treatment
Patients with hemochromatosis

The study is conducted with mononuclear cells obtained from patients undergoing phlebotomy as part of a hemochromatosis treatment.

The blood samples will be recovered immediately after their completion. 40 mL of blood will be collected and the mononuclear cells separated using a ficoll gradient.

Cell pharmacokinetics of tacrolimus

Biological: Cell pharmacokinetics of tacrolimus

Three levels of tacrolimus will be tested. Each aliquot will be supplemented with an amount of tacrolimus to achieve one of these three levels of concentration.

At 0, 5, 15, 30, 60, 120, 240mn, the samples will be separated into 2 aliquots : one dedicated to the determination of tacrolimus in mononuclear cells, the other dedicated to the determination of calcineurin activity. in mononuclear cells.

Other Name: Tacrolimus




Primary Outcome Measures :
  1. Diffusion kinetics of tacrolimus in mononuclear cells [ Time Frame: At the time of inclusion ]
    Determination of tacrolimus in mononuclear cells of subjects Tacrolimus will be assayed by mass spectrometry with a limit of quantification of 10 pg / million cells, sufficient to determine the concentrations in the volunteers' blood.


Secondary Outcome Measures :
  1. Determination of the activity of calcineurin in mononuclear cells [ Time Frame: At the time of inclusion ]

    These determinations will be carried out by Dr. Benoit Blanchet according to a validated and published method (cf references Blanchet et al, 2003; Blanchet et al, 2006).

    The method is based on high pressure liquid chromatography (HPLC coupled) with spectrophotometric detection.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients undergoing phlebotomy as part of a hemochromatosis treatment
Criteria

Inclusion Criteria:

  • adult (age > 18 years old);
  • phlebotomy as part of the maintenance treatment of hemochromatosis;
  • having received the information on the protocol and not having indicated his opposition to participate;
  • not receiving immunosuppressive therapy;
  • not receiving drug treatment that can induce or inhibit the protein ABCB1 (Rifampicin, Carbamazepine, Phenobarbital, Phenytoin, Efavirenz, Amiodarone, azole antifungals, calcium channel blockers).

Exclusion Criteria:

  • participation in another protocol whose procedures are incompatible with the realization of the study;
  • adults who are subject to legal protection (protection of justice, guardianship) and persons deprived of their liberty;
  • pregnant women.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03654794


Locations
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France
CHU de Rennes
Rennes, France, 35033
Sponsors and Collaborators
Rennes University Hospital
Investigators
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Study Director: Florian LEMAITRE, MD Rennes University Hospital

Publications:
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Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT03654794     History of Changes
Other Study ID Numbers: LOC/13-11
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: September 3, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Rennes University Hospital:
Tacrolimus
Pharmacokinetics
Additional relevant MeSH terms:
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Hemochromatosis
Metal Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Iron Overload
Iron Metabolism Disorders
Metabolic Diseases
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action