TACrolimus in Renal Transplantation: Individualization by Pharmacogenetic

• Status: Completed
• Trial end date: 2008-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Renal transplantation is the treatment of choice of the chronic renal insufficiency arrived at its final stage. Tacrolimus is an immunosuppressant treatment used for the prevention of episodes of acute rejection. Tacrolimus is characterized by a narrow therapeutic index and important interindividual variations of its pharmacokinetic characteristics. Proteins CYP3A4 and CYP3A5 are responsible of intestinal and hepatic metabolism of Tacrolimus. Various polymorphisms for CYP3A5 and CYP3A4 were described and several retrospective studies suggested an association between a genetic polymorphism of CYP3A5 and the pharmacokinetic parameters of Tacrolimus. In particular, we showed that the presence of an allele CYP3A5*1 was associated to the use of more important amounts of Tacrolimus to obtain the desired blood concentrations.

This study is a national, multicentric, prospective, opened, randomized on two arms of treatment. 280 receivers of a renal transplant in 12 centres will be included. The genotyping of gene CYP3A5 will be carried out in the 6 days following transplantation. During the first week, the patients will be treated by basiliximab, MMF and corticosteroids. They will be randomized (central randomization) in D6 to receive either Tacrolimus at 0.2 mg/kg/d, or at a dosage adapted to their genotype. After determination of the first residual blood concentration of Tacrolimus realized after six oral intakes, the daily amounts of Tacrolimus could be modified if necessary to reach the desired blood concentrations. The total duration of the study for a patient is 3 months after transplantation.

The objective of this study is to evaluate the impact of the adaptation, according to the genotype of the CYP3A5 of the patient, of the first amount of Tacrolimus on the first residual blood concentration of Tacrolimus, keeping in mind the aim of the individualization of dosage schedule by pharmacogenetic approach.

Principal criterion : Comparison, between the two groups, of the percentage of patients for whom the first blood concentration of Tacrolimus evaluated 3 days (D10) after the first administration of Tacrolimus ranges between 10 and 15 ng/ml.

Statistics will be carried out in intention to treat. The principal criterion will be analyzed by the test of chi-2.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Centre Hospitalier Universitaire, Amiens
• Collaborators: Astellas Pharma Inc; Roche Pharma AG
• Treatments: Tacrolimus

Criteria

Inclusion Criteria:

• Patients, male or female, 18 to 65 years old.

• Patients receiving a first or a second isolated renal graft coming from a donor alive or deceased,

• The patients in age to procreate must have a negative test of pregnancy before being included in this study and will have to agree to use effective contraceptive measurements throughout the study.

-Patients able to include/understand the aims and the risks of the study, -having been fully informed and having given their writing consent to take part in this study. Patients unable to write and/or read but having fully understood the oral information given by the investigator and having given their oral consent in the presence of an independent witness. -

Exclusion Criteria:

• Patients who receive several grafts.

• Patients requiring a treatment by azathioprin.

• Pregnant woman or nursing mother

• Patients receiving an incompatible graft ABO.

• Patients receiving or requiring immunosuppressant drugs prohibited by the protocol.

• Patients with a peak of historical antibody equal to or greater than 50% of the panel.

• Patients suffering from serious gastro-intestinal disorders which interfere with their capacity to receive or to absorb an oral form and patients presenting severe diarrhoea.

• Patients with symptomatic GI ulcer HIV or HTLV1 positive patients or their donors

• Patients presenting or having presented in the 5 last years one or several malignant tumours, except baso or spinocellular cutaneous epithelioma successfully treated.

• Patients with systemic infections requiring a treatment at the entry in the study.

• Patients having a leukocyte numeration lower than 2,5.109/l or haemoglobin lower than 5g/dl.

• Patients with drug-addiction whatever it is, or psychiatric disorder which, according to the point of view of the investigator, could invalidate the communication with investigator or interfere with the compliance of the patient.

• Patients who take part simultaneously in another therapeutic test or who received a study treatment less than 30 days before the entry in this study.

• Patients having already been included in this study.

• Patients allergic or intolerant with corticoids, macrolides, Tacrolimus, mycophenolate mofetil or basiliximab