Development and Validation of New LC-MS/MS Method for Determination of Unbound Tacrolimus in Plasma in CYP3A5 Expressors and Non-Expressors
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 380
- 试验地点
- 1
- 主要终点
- Development and validation of the new LC-MS/MS measurement method
研究概览
简要总结
Tacrolimus (TAC) is characterized by a narrow therapeutic window, as well as high inter- and intra-individual variability in pharmacokinetics. Both under- and overexposure may lead to severe adverse effects. Therapeutic drug monitoring (TDM) is an essential element of post-transplant patient care. Most transplantation centers use C0 to adjust TAC dosage. Some controversies remain about relationship between C0 and clinical outcome.
It is generally accepted that only protein-unbound drug molecules can cross cellular membranes, which imply that TDM of free tacrolimus fraction may be of paramount importance and improve clinical management of organ recipients.
Whole blood TAC concentrations and dose requirements are strongly associated with CYP3A5 polymorphism. Routine CYP3A5 genotyping on the waiting lists might be useful to guide tacrolimus dosing.
This interdisciplinary project tackles the research problem from three angles - biochemistry, genetics and clinical observation. The primary goal of the study is to evaluate clinical usefulness of different TDM protocols in patients after kidney and liver transplantation.
详细描述
As there are over 15.000 patients in Poland on continuous tacrolimus (TAC) therapy, the identification and validation of more sensitive and specific biomarkers is of utmost importance. The investigators propose a multiple step assessment of TAC therapeutic drug monitoring (TDM) in kidney and liver recipients. A role of genetic profiling on drug concentration and clinical effects will also be addressed. The project will significantly contribute to understanding tacrolimus pharmacokinetics and body response to drug exposure. Moreover, the proposed project is the first attempt to integrate both different TDM measure methods and patient genetics in a rigorous, prospective study with the assessment of the clinical over- and underexposure TAC effects. It is expected to provide an argument for implementation of even more personalized, predictable immunosuppressive therapy.
The investigators hypothesize that:
- There is a correlation of free TAC level with drug toxicity on one hand, and graft rejection and underimmunosuppression despite target whole blood concentration on the other.
- CYP3A5 expressors and non-expressors will present different levels of TAC in both whole blood C0 and free TAC C0 as well as different effectiveness and toxicity profiles.
- The concentration of free TAC is related to changes in the concentration of blood components, thus it is possible to derive the equation for calculating free TAC concentration as a useful tool for the drug dosage adjustment
Study design
Objectives:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •adult (>18 yo), recipient of kidney or liver transplant from the Regional Qualification Center, tacrolimus-based immunosuppression
排除标准
- •the use of agents significantly influencing TAC metabolism, double organ recipients, HBV, HCV and HIV infection, neurological disorders.
研究组 & 干预措施
De novo renal/liver transplant recipients
The group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney or liver transplant from the Regional Qualification Center (Warsaw, Poland).
干预措施: Tacrolimus (Drug)
De novo renal/liver transplant recipients
The group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney or liver transplant from the Regional Qualification Center (Warsaw, Poland).
干预措施: Unbound tacrolimus measurement (Diagnostic Test)
De novo renal/liver transplant recipients
The group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney or liver transplant from the Regional Qualification Center (Warsaw, Poland).
干预措施: CYP3A4 and CYP3A5 genotyping (Diagnostic Test)
Random renal transplant recipients
The group of 300 random adult (age > 18 years) male and female recipients of deceased kidney attending the local outpatient clinic.
干预措施: Tacrolimus (Drug)
Random renal transplant recipients
The group of 300 random adult (age > 18 years) male and female recipients of deceased kidney attending the local outpatient clinic.
干预措施: Unbound tacrolimus measurement (Diagnostic Test)
Random renal transplant recipients
The group of 300 random adult (age > 18 years) male and female recipients of deceased kidney attending the local outpatient clinic.
干预措施: CYP3A4 and CYP3A5 genotyping (Diagnostic Test)
Renal transplant recipients experiencing graft rejection
The group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney experiencing acute rejection of the renal allograft.
干预措施: Tacrolimus (Drug)
Renal transplant recipients experiencing graft rejection
The group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney experiencing acute rejection of the renal allograft.
干预措施: Unbound tacrolimus measurement (Diagnostic Test)
Renal transplant recipients experiencing graft rejection
The group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney experiencing acute rejection of the renal allograft.
干预措施: CYP3A4 and CYP3A5 genotyping (Diagnostic Test)
结局指标
主要结局
Development and validation of the new LC-MS/MS measurement method
时间窗: 1 year
Development and validation of the extremely sensitive method for unbound tacrolimus determination using the EMA and FDA guidelines
Equation to calculate unbound TAC concentration
时间窗: 1 year
Development of the equation (using the concentration of free TAC, plasma and whole blood, and blood components) by statistical methods.
A comparison of different TAC TDM protocols depending on the matrix
时间窗: 1 year
1. concentration of unbound tacrolimus in plasma ultrafiltrate 2. concentration of tacrolimus in plasma 3. concentration of tacrolimus in whole blood The measures will be obtained with the use of LC-MS/MS method.
A correlation between free TAC and symptoms of underimmunosuppresion
时间窗: 1 year
Biopsy proven acute rejection
次要结局
- A correlation between free TAC and nephrotoxicity(1 year)
- CYP3A expression(1 year)
- Blood components(1 year)
研究者
Karola Warzyszyńska
Medical Doctor
National Science Centre, Poland