Kidney Transplant Clinical Trial
Official title:
Impact of CYP3A5 Genetic Polymorphisms on Tacrolimus Concentration and Transplant Outcomes During The Early Stage Post-Transplantation in Thai Kidney Transplant Recipients
Tacrolimus is a drug used commonly in kidney transplant patients to prevent graft rejection.
Tacrolimus acts in a very narrow range in the blood for its optimum activity. If the levels
are too high, there is a risk of kidney injury, whereas, if the levels are too low there is
a higher risk of rejection and graft loss. Genetic differences in the gene coding for the
enzyme cytochrome P450 (CYP3A5), which is responsible for breaking down active tacrolimus
can contribute to variations in blood levels of tacrolimus among different individuals
taking the same dose of the drug. Certain genetic types lead to low concentrations, whereas
certain genetic types can lead to high levels. The proportion of individuals with different
types of genetic variations differ among different ethnic populations. Limited data are
available in Thai subjects or on the risk have having certain types of genetic variations on
the risk of rejection.
This study aims to compare the effects of different types of CYP3A5 gene variations on
Tacrolimus drug levels and risk of acute rejection in Thais.
Rationale important theory or hypothesis:
Tacrolimus, a potent calcineurin inhibitor, is commonly used in kidney transplant patients
worldwide. Tacrolimus has a narrow therapeutic index. Overdosing increases the risk of
dose-related adverse drug reactions and infections, whereas underdosing increases the risk
of rejection and graft loss. In addition, achieving therapeutic tacrolimus levels is
complicated by high intra- and inter-individual pharmacokinetic variability of the drug.
Though, the source of pharmacokinetic variability of tacrolimus is not fully understood. It
is known that the inter-individual variation in metabolism of tacrolimus is at least partly
due to differences in expression of the cytochrome P450 (CYP) 3A5 enzyme, one of the key
proteins involved in tacrolimus systematic clearance.
Mutations due to single nucleotide polymorphism (SNP) of the gene encoding CYP 3A5 have been
demonstrated to affect their expression. Among CYP3A5 alleles, CYP3A5*1 has been found to be
the main allele associated with CYP 3A5 expression, whereas the mutant allele CYP3A5*3
prevents expression of the enzyme. Several studies have shown that this mutation affects the
dosing of tacrolimus.
The frequency of CYP3A5 SNP varies among different ethnic populations . In a small study in
Thais, the frequency of , CYP3A5*1/*1 genotyping was identified in 20.6% of patients,
CYP3A5*1/*3 in 35.3% and CYP3A5*3/*3 in 44.1%.
To the best of our knowledge, there is no previous study on the impacts of the CYP 3A5
genetic polymorphisms on tacrolimus blood concentration and acute rejection rate during the
very early stage post-transplantation in Thai kidney transplant recipients. Evaluation of
CYP3A5 polymorphisms may be helpful in determining an appropriate starting dose, timely
achieving target levels, and improving outcomes of tacrolimus-based therapy in this group of
patients.
Therefore, we are to determine the impacts of CYP 3A5 genetic polymorphisms on tacrolimus
trough blood concentration during the first post-operative week and acute rejection rate at
3-month post-transplantation comparing between CYP3A5 expressers (CYP3A5*1 homozygotes or
heterozygotes) and CYP3A5 non-expressers (CYP3A5*3 homozygotes).
Methods:
Study population:
This retrospective analytical study will be performed at Ramathibodi hospital, Bangkok,
Thailand. Thai recipients who underwent kidney transplantation between January 2011 and
December 2013.
Data collection:
Demographics and clinical data will be gathered from the medical files and records. Blood
samples will be collected for determination of genotypes of CYP3A5, other metabolic enzymes
and transport proteins with respect to their corresponding effects on the pharmacokinetics
of tacrolimus.
Approval for this study will be obtained from the ethics committee of Ramathibodi hospital,
Faculty of Medicine, Mahidol University.
Number of samples:
According to the study of Sang-Il Min, et al , the effect of CYP3A5*1 allele with early
acute rejection and graft function in patients with kidney transplants who received
tacrolimus. CYP3A5 expressers (n=29) had the mean trough concentration to dose ratio of
127.09 ± 69.40 ng/mL/mg/kg. While CYP3A5 non-expressers (n=33) had the mean trough
concentration to dose ratio of 220.99 ± 108.95 ng/mL/mg/kg on day 10 after kidney
transplantation.
The sample size is estimated using the formula: n/group=2(Zα + Zβ)2σ2/(µ1-µ2)2 Given dose
adjusted Co of Tac among expressor µ1= 127.09±69.40 and the different at least 25% would
have clinical significant so the absolute different was 30. Calculated sample size was at
least 85 patients per group so the total subjects would be at least 170 patients.
Ref. Transplantation 2010;90: 1394-1400
Statistical analysis:
Differences in genotype will be assessed using SPSS version 17.0 software for chi square or
Mann-Whitney U tests.
;
Observational Model: Cohort, Time Perspective: Retrospective
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT04087720 -
Study of Pegloticase in Participants With Uncontrolled Gout Who Have Had a Kidney Transplant
|
Phase 4 | |
Completed |
NCT03749356 -
Study to Evaluate the Efficacy and Safety of Once-Daily Tacrolimus in Kidney Transplant Recipients
|
Phase 4 | |
Withdrawn |
NCT05811468 -
Study Correlation Between Blood, Tissue Gene Expression, Donor Derived Cell Free DNA and Histopathology in Kidney Transplant Recipients
|
||
Completed |
NCT03527238 -
Optimizing Immunosuppression Drug Dosing Via Phenotypic Precision Medicine
|
Phase 2 | |
Completed |
NCT00498576 -
Melatonin and Adiponectin in Hypertensive Kidney Transplant
|
N/A | |
Completed |
NCT00642655 -
Rituximab and Intravenous Immunoglobulin (IVIG) for Desensitization in Renal Transplantation
|
Phase 1/Phase 2 | |
Completed |
NCT00374400 -
The Paired Donation Consortium Paired Donation Program
|
N/A | |
Completed |
NCT01710033 -
A Study Of CP-690,550 In Stable Kidney Transplant Patients
|
Phase 1 | |
Completed |
NCT00205257 -
Prediction of Acute Rejection in Renal Transplant
|
Phase 1 | |
Completed |
NCT02711826 -
Treg Therapy in Subclinical Inflammation in Kidney Transplantation
|
Phase 1/Phase 2 | |
Withdrawn |
NCT03978494 -
Study to Compare Pharmacokinetics of Tacrolimus Prolonged-release (PR) Capsules and Advagraf® PR Capsules in Stable Kidney Transplant Patients.
|
Phase 1 | |
Completed |
NCT03837522 -
Trial to Define the Benefits and Harms of Deceased Donor Kidney Procurement Biopsies
|
N/A | |
Not yet recruiting |
NCT06025240 -
Expanding the Scope of Post-transplant HLA-specific Antibody Detection and Monitoring in Renal Transplant Recipients
|
||
Completed |
NCT05029310 -
Effects of Patiromer on Pharmacokinetics of Immunosuppresive Drugs in Renal Transplant Recipients
|
Phase 4 | |
Completed |
NCT03644485 -
Clinical Outcome of Delayed or Standard Prograf Together With Induction Therapy Followed by Conversion to Advagraf in Donation After Cardiac (or Circulatory) Death (DCD) Kidney Transplant Recipients
|
Phase 4 | |
Active, not recruiting |
NCT02409901 -
Effects of Personalized Physical Rehabilitation in Kidney Transplant Recipients
|
N/A | |
Completed |
NCT01047410 -
ACtive Care After Transplantation, the ACT Study
|
N/A | |
Completed |
NCT00940940 -
Safety and Immunogenicity of Zostavax Vaccine in Patients Undergoing Living Donor Kidney Transplantation
|
Phase 4 | |
Completed |
NCT00270712 -
A Study of Factors That Affect Long-Term Kidney Transplant Function
|
||
Completed |
NCT00217126 -
The Study of Long-term Deterioration of Kidney Transplants.
|
Phase 4 |