Impact of CYP3A5 Genetic Polymorphisms on Tacrolimus Concentration and Transplant Outcomes During The Early Stage Post-Transplantation in Thai Kidney Transplant Recipients
试验速览
- 阶段
- 不适用
- 入组人数
- 170
- 主要终点
- Trough tacrolimus blood concentration to dose ratio
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Kidney transplantation between January 2011 and December 2013
- •Received two divided daily doses of tacrolimus in their initial regimen for prevention of allograft rejection
- •Informed consent
排除标准
- •multiple organ transplantation
- •hyperacute rejection
- •non-functioning graft,
- •ABO incompatible kidney transplantation
- •severe liver function or hypoalbuminemia (serum albumin <3 g/dl)
- •severe gastrointestinal disorders that could interfere with their ability to absorb oral medications
- •patients whose recorded data is incomplete;
- •Receiving other medications that can significantly interfere with tacrolimus pharmacokinetics (except methylprednisolone and prednisolone)
结局指标
主要结局
Trough tacrolimus blood concentration to dose ratio
时间窗: 3 days after transplant
次要结局
- Proportion achieved the target trough blood concentration within the first week(7 days after transplant)
- Acute rejection rate(3 months after transplant)