Initial Dosage Range of Tacrolimus by Genotyping in Chinese Renal Transplantation

NCT00935298 | Completed Phase 4 DMC

• 2 other identifiers: 2007101620090403
• Study Type: interventional
• Target: 145
• Locations: 1 country
• Sites: 5

Brief 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

Conditions

Renal Transplantation

Keywords

Renal Transplantation; Tacrolimus; CYP3A5; Genotyping

Outcome Measures

Primary Outcomes (2)

• The time to obtain first target concentration of FK506 (8-13ng/ml)

  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)

  1w

• The proportion of patients reaching therapeutic concentration on Day 3 and 7 without dosage schedule adjustments

  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).

  1 w

Secondary Outcomes (4)

• 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

Study Arms (1)

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EXPERIMENTAL

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

Drug: Tacrolimus

Interventions

Tacrolimus DRUG

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).

Also known as: Prograf® capsules (tacrolimus)

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Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Second Artillery General Hospital: lead
• Capital Medical University: collaborator
• Shanghai Changzheng Hospital: collaborator
• Pharmacology Research Institute: collaborator
• Air Force General Hospital of the PLA: collaborator
• Health Department of General Logistics: collaborator

Study Sites (5)

Chaoyang Hospital, affiliated Hospital of Capital Medical University

Beijing, Beijing Municipality, 100020, China

Location

General Hospital of Air Force of Chinese PLA

Beijing, Beijing Municipality, 100036, China

Location

The Second Artillery Gernal Hospital

Beijing, Beijing Municipality, 100088, China

Location

The First Affiliated Hospital of Zhengzhou University

Zhengzhou, Henan, 450052, China

Location

Changzheng Hospital, the Second Affiliated Hospital of the Second Military Medical University

Shanghai, Shanghai Municipality, 200003, China

Location

MeSH Terms

Interventions

Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• LIHong LIU, MD Ph.D

  The Second Artillery Genaral Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2009
• First Posted: July 9, 2009
• Study Start: July 1, 2009
• Primary Completion: December 1, 2010
• Study Completion: June 1, 2011
• Last Updated: December 22, 2011

Record last verified: 2011-12

Locations

CN (5)