Clinical trial NCT03654794: Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells
Official title: Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hemochromatosis
Keywords: Tacrolimus
Pharmacokinetics
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2018-08-31
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients undergoing phlebotomy as part of a hemochromatosis treatment

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

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.

Eligibility 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.

Primary outcomes:
measure: Diffusion kinetics of tacrolimus in mononuclear cells
timeFrame: At the time of inclusion
Secondary outcomes:
measure: Determination of the activity of calcineurin in mononuclear cells
timeFrame: At the time of inclusion
Other outcomes:
Locations:
city: Rennes
country: France
facility: CHU de Rennes
Study officials:
affiliation: Rennes University Hospital
name: Florian LEMAITRE, MD
role: STUDY_DIRECTOR
References:
citation: Blanchet B, Hulin A, Duvoux C, Astier A. Determination of serine/threonine protein phosphatase type 2B PP2B in lymphocytes by HPLC. Anal Biochem. 2003 Jan 1;312(1):1-6. doi: 10.1016/s0003-2697(02)00214-2.
citation: Blanchet B, Hulin A, Ghaleh B, Giraudier S, Jouault H, Astier A. Distribution of calcineurin activity in blood cell fractions and impact of tacrolimus inhibition. Fundam Clin Pharmacol. 2006 Apr;20(2):137-44. doi: 10.1111/j.1472-8206.2006.00399.x.