Initial Dosage Range of Tacrolimus by Genotyping in Chinese Renal Transplantation
Condition: Renal Transplantation
Study type: Interventional
Phase: Phase 4

Summary: 
      Acute rejection (AR) is the main complication after transplantation, which is a severe risk
      of chronic rejection and implant devitalization.

      Tacrolimus (FK506) is an immunosuppressant 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.

      Tacrolimus is metabolized through the liver by the cytochrome P450 system, the cytochrome
      P450 3A5 (CYP 3A5) isoenzyme specifically. Polymorphisms in the CYP 3A5 gene have been
      associated with changes in metabolic function of the translated isoenzyme. These
      polymorphisms result in metabolism acceleration of tacrolimus as compared to subjects having
      the wild type gene, consequently leading to insufficiency of tacrolimus; it is theorized that
      this leads to higher risk of acute rejection. Several retrospective studies suggested an
      association between a genetic polymorphism of CYP3A5 and the interindividual variations of
      tacrolimus blood concentration. In particular, our initial study showed that adult renal
      transplant recipients with the CYP3A5*1/*3 and *1/*1 （expressors） genotype require higher,
      fixed, starting dose compared with CYP3A5*3/*3 （nonexpressor）to reach the predefined target
      exposure early after transplantation.

      This prospective study is designed to evaluate whether genetic testing of CYP 3A5 can improve
      tacrolimus initiation better than usual care. This study is a prospective, multicentric,
      open, parallel , efficacy study. 300 receivers of a renal transplant in 8 centres will be
      included.

      The genotyping of gene CYP3A5 will be carried out in the 4-7days before renal
      transplantation. After transplantation, the patients will be treated by MMF, corticosteroids
      and tacrolimus at a dosage adapted to their genotype(0.15mg/kg/d for CYP3A5*1/*1 type and
      CYP3A5*1/*3 type，0.08mg/kg/d for CYP3A5*3/*3 type).

      The determination of tacrolimus blood concentration will be carried out on Day
      3,5,7,14,18,21,28,35,49,63,77,90. 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 determine the initial dosage of tacrolimus in Chinese renal
      transplantation patients by genotyping of the cytochrome P450 3A5
    

Detailed description: 
      VISITS

      The participation of the patient in this study will be 3 months. For this period, 9 visits
      are planned

      •Before transplantation

      Visit 1: inclusion visit(in the 4-7 days before transplantation),A blood taking will be
      carried out on EDTA tube for CYP 3A5 genotyping in the 4-7 days before renal transplantation.

      • After transplantation

      Visit 2: D3

      Visit 3: D5

      Visit 4: D7

      Visit 5: D14

      Visit 6: D21

      Visit 7: M1 + - 3 days

      Visit 8: M2 + - 3 days

      Visit 9: M3 + - 3 days

      Treatment

      After transplantation, the patients will be treated by MMF, corticosteroids and tacrolimus at
      a dosage adapted to their genotype(CYP3A5*1/*1 type and CYP3A5*1/*3 type administer
      0.15mg/kg/d，CYP3A5*3/*3 type administer 0.08mg/kg/d).

      The MMF will be given according to weight in 3 months after transplantation as follows:

      below 50 kilogram(kg) 0.25g bid (0.5g pre day)

      50~70kg 0.50g bid (1.0g pre day)

      70~90kg 0.75g bid (1.5g pre day)

      Exceed 90kg 1.0g bid (2.0g pre day)

      Corticosteroid therapy in decreasing amount as follows:

      D0 - D15: 20 Mg

      D16 - D30: 15 Mg

      D30 - D45: 10 Mg

      D46 - M3 5 Mg

      The determination of tacrolimus blood concentration will be carried out on Day
      3,5,7,14,18,21,28,35,49,63,77,90. 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.

      If the present study is able to confirm an advantage for a genotype-driven algorithm, in
      terms of improved efficiency, therapeutic efficacy, especially, safety, a pharmacogenetics
      approach to dosing can be recommended as the basis wide quality improvement initiative that
      should improve patient outcomes, reduce resource use (costs of achieving safe and therapeutic
      immunosuppression), and reduce adverse clinical events.
    

Intervention name(s): Tacrolimus
Intervention type(s): Drug
Intervention description(s): The genotyping of gene CYP3A5 will be carried out in the 4-7days before renal transplantation. After transplantation, the patients will be treated by MMF, corticosteroids and tacrolimus at a dosage adapted to their genotype(CYP3A5*1/*1 type and CYP3A5*1/*3 type administer 0.15mg/kg/d，CYP3A5*3/*3 type administer 0.08mg/kg/d).
Other intervention name(s): Prograf® capsules (tacrolimus)
Intervention MeSH terms: Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Renal Transplantation; Tacrolimus; CYP3A5; Genotyping