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.

NCT06361732 | Recruiting

• 1 other identifier: ILBS-liver Transplant-03
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 1

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 (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.

Conditions

Pediatric Liver Transplant

Outcome Measures

Primary Outcomes (1)

• 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.

  1 year

Secondary Outcomes (9)

• Prevalence of CYP3A5 alleles in the donors of pediatric liver transplant recipients.

  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.

  Day 0

• Prevalence of ABCB1 3435 C/T alleles in the recipients of pediatric liver transplant.

  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.

  1 week, 4 weeks, 3 months & 6 months and 1 year.

• Comparison of the Number of Rejection episodes 1 year from LT.

  1 year

Study Arms (1)

Liver Transplant

Liver Transplant

Other: No intervention

Interventions

No intervention OTHER

No intervention

Liver Transplant

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

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.

You may qualify if:

• \- 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Institute of Liver and Biliary Sciences, India: lead

Study Sites (1)

Institute of Liver and Biliary Sciences

New Delhi, 110070, India

RECRUITING

Central Study Contacts

Dr Snigdha Verma, MD

CONTACT

01146300000; dr.snigdha1@gmail.com

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2024
• First Posted: April 12, 2024
• Study Start: December 17, 2022
• Primary Completion: October 30, 2024
• Study Completion: October 30, 2024
• Last Updated: April 12, 2024

Record last verified: 2024-04

Locations

IN (1)