Clinical trial NCT02377791: Impact of CYP3A5 Gene Polymorphisms on Tacrolimus Concentrations and Outcomes in Thai Transplant Recipients
Official title: Impact of CYP3A5 Genetic Polymorphisms on Tacrolimus Concentration and Transplant Outcomes During The Early Stage Post-Transplantation in Thai Kidney Transplant Recipients
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Kidney Transplant
Keywords: tacrolimus
Cytochrome P-450 CYP3A
Kidney transplant
FK506
Prograf
Rejection
Gene Polymorphism
Lead sponsor: Mahidol University
Sponsor class: OTHER
Collaborators: name: Astellas Pharma Inc
First posted: 2015-03-04
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Thai recipients who underwent kidney transplantation between January 2011 and December 2013 and were receiving two divided daily doses of tacrolimus in their initial regimen for prevention of allograft rejection

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Kidney transplantation between January 2011 and December 2013
2. Received two divided daily doses of tacrolimus in their initial regimen for prevention of allograft rejection
3. Informed consent

Exclusion Criteria:

1. multiple organ transplantation
2. hyperacute rejection
3. non-functioning graft,
4. ABO incompatible kidney transplantation
5. severe liver function or hypoalbuminemia (serum albumin \<3 g/dl)
6. severe gastrointestinal disorders that could interfere with their ability to absorb oral medications
7. patients whose recorded data is incomplete;
8. Receiving other medications that can significantly interfere with tacrolimus pharmacokinetics (except methylprednisolone and prednisolone)

Primary outcomes:
measure: Trough tacrolimus blood concentration to dose ratio
timeFrame: 3 days after transplant
Secondary outcomes:
measure: Proportion achieved the target trough blood concentration within the first week
timeFrame: 7 days after transplant
measure: Acute rejection rate
timeFrame: 3 months after transplant
Other outcomes:
Locations:
Study officials:
affiliation: Ramathibodi Hospital, Faculty of Medicine, Mahidol University
name: Chagriya Kitiyakara, MD
role: STUDY_CHAIR
References:
citation: Yaowakulpatana K, Vadcharavivad S, Ingsathit A, Areepium N, Kantachuvesiri S, Phakdeekitcharoen B, Sukasem C, Sra-Ium S, Sumethkul V, Kitiyakara C. Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation. Eur J Clin Pharmacol. 2016 Mar;72(3):277-83. doi: 10.1007/s00228-015-1990-0. Epub 2015 Dec 4.