Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells

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

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Key information

Conditions

Hemochromatosis Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Iron Metabolism Disorders Iron Overload Metabolic Diseases Metabolism, Inborn Errors Metal Metabolism, Inborn Errors Nutritional and Metabolic Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

CHU de Rennes

Rennes, 35033, France

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Cell pharmacokinetics of tacrolimus

Biological

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 names: Tacrolimus

Primary outcomes

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 outcomes

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.

Sponsors and collaborators

Lead sponsor

Rennes University Hospital

Other

Registry information

Acronym: DIFF-TAC

Important dates

Study start: 2013
Primary completion: 2017
Study completion: 2017
First posted: Aug 31, 2018
Registry last updated: Sep 4, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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Completed