Ignite Creation Date:
2024-05-06 @ 8:23 PM
Last Modification Date:
2024-10-26 @ 3:26 PM
Study NCT ID:
NCT06361732
Status:
RECRUITING
Last Update Posted:
2024-04-12
First Post:
2024-04-08
Brief Title:
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
Sponsor:
Institute of Liver and Biliary Sciences India
Organization:
Institute of Liver and Biliary Sciences India
Study Overview
Official Title:
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
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 24 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 concentrationweight-adjusted dose CW-D ratio in the body The wild type CYP3A53 are slow metabolizers and mutant ones CYP3A5 11 and CYP3A5 13 are fast metabolizers Fast
metabolizers have a low CW-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 c3435CT are also known to influence tacrolimus dosage in the first week of transplant CD 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
metabolizers have a low CW-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 c3435CT are also known to influence tacrolimus dosage in the first week of transplant CD 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
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 15 times ULN 60 IUL in the pediatric Liver transplant recipients with grafts from slow metabolizer CYP3A533 allele versus fast metabolizer CYP3A513 and 11 alleles donors
Study population All donors and recipients of Pediatric Liver transplant recipients 0-18 yearsfrom 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 CD levels graft functions ASTALT Toxicities of Tacrolimusneurologicalmetabolic 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 33 31 and 11 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 Fishers exact test and students 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 005
Adverse effects No such adverse events are involved in the study
Primary objective To compare the time in days to achieve transaminases within 15 times ULN 60 IUL in the pediatric Liver transplant recipients with grafts from slow metabolizer CYP3A533 allele versus fast metabolizer CYP3A513 and 11 alleles donors
Study population All donors and recipients of Pediatric Liver transplant recipients 0-18 yearsfrom 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 CD levels graft functions ASTALT Toxicities of Tacrolimusneurologicalmetabolic 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 33 31 and 11 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 Fishers exact test and students 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 005
Adverse effects No such adverse events are involved in the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None