- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT06361732
Prevalence of CYP3A5 Polymorphisms in the Donors and ABCB1 Polymorphisms in the Recipients Undergoing Pediatric Liver Transplant and Their Influence on Tacrolimus Levels and Graft Function.
It is known that Immunosuppression post-Liver transplant is central to achieving optimal outcomes in liver transplant recipients. It is required to maintain an adequate balance between reducing rejection and toxicities. Mainstay drugs for maintenance therapy are Calcinuerin inhibitors - Tacrolimus versus cyclosporine. Tacrolimus is preferred, as it has less rejection and better graft survival. However, there is risk of renal and metabolic toxicities. Tacrolimus is bound mainly to alpha1-acid-glycoprotein (encoded by the ABCB1gene) expressed on various epithelial and endothelial cells and lymphocytes. Elimination occurs by metabolizing enzymes of cytochrome P450 system, with biliary excretion (95%) of metabolites (majority) with minority through urine (2.4%). Demethylation and hydroxylation of tacrolimus occurs by hepatic and intestinal CYP3A isoforms (CYP3A4 and CYP3A5). Among the factors that play an important role in the pharmacokinetics of tacrolimus, thus affecting the tacrolimus trough levels in the body and in turn influencing the dosing of the drug required to maintain an adequate balance between reducing rejection and toxicities, genetics plays an important role. Increased expression of CYP3A5 causes more metabolism of tacrolimus and hence affecting the tacrolimus concentration/weight-adjusted dose (C/W-D) ratio in the body. The wild type (CYP3A5*3) are slow metabolizers and mutant ones (CYP3A5 *1/*1 and CYP3A5 *1/*3) are fast metabolizers. Fast
metabolizers have a low C/W-D ratio and require higher Tacrolimus dosing and are thus susceptible to renal and metabolic toxicities, EBV viremia and post transplant lymphoproliferative disorder. Polymorphisms in ABCB1 (c.3435C>T) are also known to influence tacrolimus dosage in the first week of transplant (C/D ratio was lower in ABCB1 3435CC in comparison to CT and TT). There is no such data in pediatric liver transplant setting from Indian subcontinent. The aim of the study is to study the prevalence of CYP3A5 polymorphisms in the donors and ABCB1 polymorphisms in the recipients undergoing Paediatric liver transplant and their influence on Tacrolimus levels and graft function.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Aim: To study the prevalence of CYP3A5 polymorphisms in the donors and ABCB1 polymorphisms in the recipients undergoing Paediatric liver transplant and their influence on Tacrolimus levels and graft function.
Primary objective: To compare the time (in days) to achieve transaminases within 1.5 times ULN (60 IU/L) in the pediatric Liver transplant recipients with grafts from slow metabolizer (CYP3A5*3/3 allele) versus fast metabolizer (CYP3A5*1/3 and 1/1 alleles) donors.
Study population: All donors and recipients of Pediatric Liver transplant recipients (0-18 years),from September 2011 till October 2023, follow up atleast 1 for year.
Study design: Retrospective and Prospective. Intervention: None Monitoring and assessment: Monitoring for the Tac C/D levels, graft functions (AST/ALT) , Toxicities of Tacrolimus(neurological,metabolic) and its correlation to the CYP3A5 and ABCB1 polymorphism. This will be as per standard Institutional protocol followed up since the time of start of transplant program.
Polymorphisms in CYP3A5 and ABCB1: Whole blood samples will be collected for donors and recipients in the EDTA vials. DNA extraction will be done as per the standard procedure followed in
the department. Genotype analysis for CYP3A5 (3/3, 3/1 and 1/1) and ABCB1 3435 (CC, CT & TT) alleles will be done by polymerase chain reaction (PCR) amplification and will be detected by restriction fragment length polymorphism (RFLP) analysis.
Statistical Analysis: All the categorical variables will be expressed as frequencies, whereas continuous ones will be expressed as mean+ SD or median (IQR). Chi-square , Fisher's exact test and student's t-test will be applied for assessment of causality. Kaplan-Meier statistics will be done for survival and liver related morbidity besides this an appropriate analysis will be carried out at the time of data analysis like diagnostic test, logistic regression etc. Significance will be mentioned in the form of p-value <0.05.
Adverse effects: No such adverse events are involved in the study
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Dr Snigdha Verma, MD
- Phone Number: 01146300000
- Email: dr.snigdha1@gmail.com
Study Locations
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-
-
New Delhi, India, 110070
- Recruiting
- Institute of liver and Biliary Sciences
-
Contact:
- Dr Snigdha Verma, MD
- Phone Number: 01146300000
- Email: dr.snigdha1@gmail.com
-
Contact:
- Dr Rajeev Khanna, MD
- Phone Number: 01146300000
- Email: drrajeev_khanna@rediffmail.com
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion Criteria:
- All Pediatric Living donor liver Transpalnt Liver transplant recipients (0-18 years of age) from September 2011 till October 2023 with follow-up at least for 1 year.
Exclusion Criteria:
- Incomplete medical records
- Non-availability of Donor to check CYP3A5 polymorphism Deceased donor liver transplantation
- Primary non-function
- Mortality within 2 weeks of liver transplantation Re-transplantation
- Children with Hepatitis C infection
- Multi-visceral or Combined liver-kidney transplantation
- Hepatic artery thrombosis within 6 months of liver transplantation
- Biliary complications within 6 months of liver transplantation requiring intervention
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Liver Transplant
|
No intervention
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Time (in days) to achieve transaminases within 1.5 times ULN (60 IU/L) in the pediatric Liver transplant recipients with grafts from slow metabolizer (CYP3A5*3/3 allele) versus fast metabolizer (CYP3A5*1/3 and 1/1 alleles) donors.
Time Frame: 1 year
|
1 year
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Prevalence of CYP3A5 alleles in the donors of pediatric liver transplant recipients.
Time Frame: Day 0
|
Day 0
|
Influence of donor CYP3A5 alleles (slow versus fast metabolizers) on tacrolimus concentration-weight adjusted dose ratio at 1 week, 4 weeks, 3 months & 6 months and 1 year after liver transplantation.
Time Frame: Day 0
|
Day 0
|
Prevalence of ABCB1 3435 C/T alleles in the recipients of pediatric liver transplant.
Time Frame: Day 0
|
Day 0
|
Influence of recipient ABCB1 3435 C/T on tacrolimus concentration-weight adjusted dose ratio at 1 week, 4 weeks, 3 months and 6 months and 1 year after liver transplantation.
Time Frame: 1 week, 4 weeks, 3 months & 6 months and 1 year.
|
1 week, 4 weeks, 3 months & 6 months and 1 year.
|
Comparison of the Number of Rejection episodes 1 year from LT.
Time Frame: 1 year
|
1 year
|
Comparison of proportion of patients who were withdrawn from Mycophenolate or required addition of Mycophenolate 1 year from LT.
Time Frame: 1 year
|
1 year
|
Comparison of proportion of patients with renal toxicity 1 year from LT.
Time Frame: 1 year
|
1 year
|
Comparison of proportion of patients with Neurological toxicity 1 year from LT.
Time Frame: 1 year
|
1 year
|
Comparison of e-GFRand cystatin-C levels in the two cohorts of pediatric liver transplant recipients with grafts from slow metabolizer (CYP3A5*3/3 allele) versus fast metabolizer (CYP3A5*1/3 and 1/1 alleles) donors.
Time Frame: 6 months and 1 years
|
6 months and 1 years
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Other Study ID Numbers
- ILBS-liver Transplant-03
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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