HemochromatosisDIFF-TACNCT03654794
Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells
An observational study of Hemochromatosis, run by Rennes University Hospital at 1 site in France.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hemochromatosis
- What is being tested?
- Cell pharmacokinetics of tacrolimus
- How many people
- 26 participants
- Where
- 1 siteFrance
- Study dates
- 24 Oct 2013to 6 Jul 2017
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients undergoing phlebotomy as part of a hemochromatosis treatment
Who may be able to join
- 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).
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
Read the 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.
- Conditions
- Hemochromatosis
- Being tested
- Cell pharmacokinetics of tacrolimus
- Keywords
- Tacrolimus, Pharmacokinetics
- Medical subject headings
- Hemochromatosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cell pharmacokinetics of tacrolimusBiological
Also called 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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Biological: Cell pharmacokinetics of tacrolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Diffusion kinetics of tacrolimus in mononuclear cells
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.
Measured: At the time of inclusion
Secondary outcomes (1)
Determination of the activity of calcineurin in mononuclear cells
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.
Measured: At the time of inclusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Aug 2018
- Study start24 Oct 2013
- Primary completion6 Jul 2017
- Study completion6 Jul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for HemochromatosisStudies of the same condition, open and under way.
- More trials run by Rennes University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rennes University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Florian LEMAITRE, MD, Study director, Rennes University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03654794
- Sponsor's protocol ID
- LOC/13-11
- Acronym
- DIFF-TAC
- Status last verified
- Aug 2018
- First submitted
- 28 Aug 2018
- Last updated
- 4 Sep 2018
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 12479828Blanchet 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.
PubMed 16573714
Study at a glance
From the registry record, last updated by the sponsor on 4 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Study of the Cellular Diffusion of Tacrolimus Across the Membrane of Mononuclear Cells
- ClinicalTrials.gov ID
- NCT03654794
- Acronym / sponsor ID
- DIFF-TAC / LOC/13-11
- Conditions
- Hemochromatosis
- Keywords
- Tacrolimus, Pharmacokinetics
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 26 participants (actual)
- Lead sponsor
- Rennes University HospitalUniversity, hospital or other
- Study start
- 24 Oct 2013 (actual)
- Primary completion
- 6 Jul 2017 (actual)
- Study completion
- 6 Jul 2017 (actual)
- First posted
- 31 Aug 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with hemochromatosis | – | Biological: Cell pharmacokinetics of tacrolimusThe 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients undergoing phlebotomy as part of a hemochromatosis treatment
Key inclusion criteria (5 listed)
- 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).
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cell pharmacokinetics of tacrolimusAlso: TacrolimusThree 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. | Biological | Patients with hemochromatosis |
Primary outcome
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.
1 secondary outcome
Determination of the activity of calcineurin in mononuclear cells
Time frame: At the time of inclusion
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Sep 2018.
- Background: PubMed 12479828Blanchet 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.
- Background: PubMed 16573714Blanchet 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Florian LEMAITRE, MD study director
Rennes University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hemochromatosis, run by Rennes University Hospital at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Diffusion kinetics of tacrolimus in mononuclear cells (time frame: At the time of inclusion). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03654794, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Sep 2018.