Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells (DIFF-TAC)
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|ClinicalTrials.gov Identifier: NCT03654794|
Recruitment Status : Completed
First Posted : August 31, 2018
Last Update Posted : September 3, 2018
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|
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.
|Study Type :||Observational|
|Actual Enrollment :||26 participants|
|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|
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
- 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.
- 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.
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
|CHU de Rennes|
|Rennes, France, 35033|
|Study Director:||Florian LEMAITRE, MD||Rennes University Hospital|