Pharmacokinetic of Tacrolimus in Paediatric Liver Transplant Patients

Study Overview
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Brief Summary
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Tacrolimus is the cornerstone immunosuppressant in children with liver transplantation, its use is complicated by its narrow therapeutic index and variable pharmacokinetics. This study is designed to assess the posology of tacrolimus in post-transplantation in the month after liver transplantation to obtain a therapeutic target between 10-15 ng/mL and the impact of biological and genetic factors on the pharmacokinetic parameters in paediatric liver transplant recipients.

Detailed Description
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Tacrolimus is the cornerstone immunosuppressant in children with liver transplantation, its use is complicated by its narrow therapeutic index and variable pharmacokinetics. Therapeutic drug monitoring (TDM) of tacrolimus, based on whole-blood trough concentration (C0) values, is mandatory for use of twice-daily tacrolimus (Prograf_) as in order to decrease interindividual variability in exposure and thereby minimize the risk of acute rejection and the occurrence of adverse effects (mainly nephrotoxicity and, to a lesser extent, neurotoxicity). Until now, the C0 is the easiest means of individual dose adjustment, as only one blood sample is required and the clinician can easily calculate the dose needed to reach the target. Many factors have an impact on the pharmacokinetic parameters. However the adaptation of the time to achieve the target stays an issue. Among factors of inter and intra variability of pharmacokinetic of tacrolimus, some of them are specific of the pediatric liver transplantation population. Aims: To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation.

Official Title
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Building a Population Pharmacokinetic Model of Tacrolimus in Paediatric Liver Transplant Patients

Conditions
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Liver Transplantation, Child

Intervention / Treatment
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* Other: Pharmacokinetic
* Other: Pharmacogenetic
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of children who need to have a liver transplantation : between 6 month and 12 years Formulary of consent signed by the two parents. Children who need to receive tacrolimus per os (Modigraf® ) only after liver transplantation associated to Simulect® (basilixumab) in post-transplantation immediately as main Affiliation to the system of social protection. Exclusion Criteria: Children who need a multi organs transplantation Hypersensibility or Contraindication to Modigraf® or others macrolides. Patients retransplanted in the 14 days after the transplantation Patients with multivisceral failure Patients who have an introduction of tacrolimus 3 days after transplantation Patients who need complementary immunosuppressive drugs with corticoids excepted methylprednisolone used for reject Patients who received Prograf® per os or iv. Patients who received Cellcept® or Myfortic® Opposition to sign the formulary of consent or the understand the note of information

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Pharmacokinetic and Pharmacogenetic<br>Liver Transplant Children treated with tacrolimus | Other: Pharmacokinetic<br>* Taking blood samples for an Pharmacokinetic of tacrolimus in Paediatric Liver Transplant Patients treated with tacrolimus<br>Other: Pharmacogenetic<br>* Pharmacogenetic study<br>Drug: Tacrolimus<br>* These Patients are treated with tacrolimus after the Liver Transplantation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood concentration of tacrolimus (ng/mL) | Residual concentration, Cmin, Cmax, Cl/F and Area Under the Curve of tacrolimus (AUC) | Between day2 and day4 and day 10 and day14, after day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P3A5 cytochrome (CYP3A5/4), ABCB1 genotypes of donor and recipient. |  | Up to 3 years | 
| Factor V and prothrombin time | To estimate a delayed graft function | Up to 3 years | 
| Time to achieve two concentrations of tacrolimus in the therapeutic target without change of posology |  | Up to 3 years | 
| Clinical Occurrence of adverse events (reject and/or adverse effects with tacrolimus) |  | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver transplantation, Child, Tacrolimus, Pharmacokinetic