NCT00935298

Initial Dosage Range of Tacrolimus by Genotyping in Chinese Renal Transplantation

Prospective Study:Clinical Trial on the Tacrolimus Dosage Range in Chinese Renal Transplant Recipients With Different Genetic Phenotypes of Drug Metabolizing Enzymes(CYP3A5)

• Status: Completed
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 145 (actual)
• Sponsor: The Second Artillery General Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Renal Transplantation

Interventions

Type	Name	Description
DRUG	Tacrolimus	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).

Timeline

• Start date: 2009-07-01
• Primary completion: 2010-12-01
• Completion: 2011-06-01
• First posted: 2009-07-09
• Last updated: 2011-12-22

Locations

5 sites across 1 country: China