Prospective Study:Clinical Trial on the Tacrolimus Dosage Range in Chinese Renal Transplant Recipients With Different Genetic Phenotypes of Drug Metabolizing Enzymes(CYP3A5)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 145
- 试验地点
- 5
- 主要终点
- The time to obtain first target concentration of FK506 (8-13ng/ml)
研究概览
简要总结
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
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients of renal inadequacy , necessary to receive renal transplantation , male or female , 18 to 65 years old;
- •Patients receiving a first isolated renal graft with administration of FK506;
- •Patient willing to provide informed consent prior to the specimen collection procedure.
排除标准
- •Patients who received another clinical pharmaceutical study less than 3 months before the entry in this study , and who have already completed or dropped out of this study.
- •Patients with contraindications of FK506 in immunosuppressive therapy : being in pregnancy and being allergic or intolerant with FK506 or other macrolides.
- •Patients suffering from severe diseases of cardiovascular system (essential hypertension), liver (anamnesis of type B hepatitis , type C hepatitis) , hemopoietic system , nervous system , and psychotics.
- •Patients interfered with their blood concentrations of FK506 by administration of cytochrome P4503A4 and P4503A5 enzyme inhibitors , such as lidocaine , midazolam , nicardipine , niludipine , cortisone , itraconazole , fluconazole , ketoconazole , miconazole , clotrimazole ，Bromocriptine and so on.
- •Patients having anaemia (hemoglobin lower than 7g/dl).
- •Patients Diagnosed DM.
- •Patients interfered with their capacity to absorb FK506 by anorexia nervosa , malabsorption syndrome or gastro-intestinal resection according to the viewpoint of the investigators.
- •Patients who lacks understanding of the medicinal knowledge of tacrolimus and the risks of the study according to the viewpoint of the investigators.
- •Patients with allergic constitution or a history of serious allergy.
- •Patients with bad compliance according to viewpoint of the investigators.
研究组 & 干预措施
T
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/*3 and *1/*1 ,expressors; CYP3A5*3/*3 nonexpressor）.
The objective is to determine the initial dosage Range of tacrolimus in Chinese renal transplantation patients by genotyping of the cytochrome P450 3A5
干预措施: Tacrolimus (Drug)
结局指标
主要结局
The time to obtain first target concentration of FK506 (8-13ng/ml)
时间窗: 1w
The interval time (median) after transplantation to achieve first target tacrolimus blood concentration range (7\~13ng/ml) by genotype was 7 days (3 to 28) for CYP3A5\*1/\*3\&\*1/\*1 patients (N=59) and 3 days (3 to 14) for CYP3A5 \*3/\*3 patients (N=86)
The proportion of patients reaching therapeutic concentration on Day 3 and 7 without dosage schedule adjustments
时间窗: 1 w
As compared with patients with cyp3A5\*1/\*3 (expression，n=59)，patients with the CYP3A5\*3/\*3 (nonexpression, n=86) had a decreased time to the first tacrolimus blood concentration within the therapeutic range，but had a increased proportion of patients reaching therapeutic range on Day 3-7 after tranplantration（91.8% vs. 64.4%，P = 0.021).
次要结局
- The total number of determination of FK506 therapeutic concentration (for safety, efficiency or dose insufficiency reasons)(3 months)
- After transplantation,the average daily tacrolimus dose, occurrence of acute rejection，delayed renal graft events(3months)
- Survival of the grafts at M3(3months)
- Duration of the hospitalizations during the first 3 months(3 months)