Tacrolimus Pharmacokinetic Subpopulations: Prospective Mechanistic Investigations of the Tacrolimus C/D Ratio
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 180
- 试验地点
- 2
- 主要终点
- Tacrolimus metabolite concentration
研究概览
简要总结
This prospective study will investigate the concentrations of tacrolimus metabolites (M-I and M-III) over the four first years post-transplantation.
A differential metabolism might result in different metabolites' concentration and explain a kidney survival difference between "high rate metabolism" (defined as a concentration/dose ratio, C/D ratio, lower than 1.04 µg/l/mg) and other patients.
The primary endpoint is therefore to compare tacrolimus metabolites' concentrations with respect to the group, either < or >= 1.04 µg/l/mg, in order to detect differences in tacrolimus metabolization between these groups.
详细描述
Tacrolimus is the cornerstone of immunosuppression in renal transplantation, but its nephrotoxicity, in particular, makes it a drug with a narrow therapeutic range, requiring regular pharmacokinetic monitoring. Several studies have demonstrated a relationship between concentration (residual tacrolimus) and dose (prescribed daily tacrolimus) ratio, or C/D ratio, and graft survival. "Fast metabolizers" have been identified by a C/D ratio of less than 1.05 and have poorer graft survival than other renal transplant recipients. The determinants of the C/D ratio (the clinical or biological factors influencing the C/D ratio) are not known.
The purpose of the TIPS study is to prospectively identify tacrolimus metabolism patterns, based on the C/D ratio, and to identify the determinants of the C/D ratio.
The investigators assumed that different metabolism profiles are associated with different degradation profiles of tacrolimus. These degradation profiles can be identified by analysis of known plasma metabolites of tacrolimus (M-I and M-III) and by pharmacogenetic analysis of genes involved in the metabolism of tacrolimus. Also, since the pharmacokinetic profile can be associated with the therapeutic strategy (prolonged-release vs. immediate-release tacrolimus form), it will be investigated in the study in parallel. The hypothesis of this work is that the pharmacokinetic parameters of tacrolimus and its metabolites are associated with renal transplant survival and simultaneously with the therapeutic strategy of the drug. The investigators hope that this will explain the relationship between the C/D ratio of tacrolimus and graft survival, in order to tailor tacrolimus treatment to individual patients (adaptation of the therapeutic strategy, choice of optimal dose).
For this prospective tri-centric randomized prospective study, new renal transplant patients who are scheduled to receive immunosuppression including tacrolimus will be included and randomized between two therapeutic strategies (prolonged-release vs. immediate-release tacrolimus form) within 7 days after transplantation. Patients will be followed for 4 years. Regular consultations will be provided (W6, M3, M6, M12, M24, M36 and M48) including usual biological analyses for renal transplant follow-up, full prescriptions and adherence questionnaire (BAASIS) but also a systematic biopsy of the renal transplant (M3 and M12) and an abbreviated pharmacokinetic study of tacrolimus exposure (M3).
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
- •Kidney transplant patients at the CHUGA, CHU Saint-Etienne or CHU Clermont-Ferrand, whose new transplant is no more than 7 days old (inclusive)
- •Patients initially treated with tacrolimus as an immunosuppressant, combined with mycophenolate (MMF), mycophenolic acid (MPA) or everolimus (EVR), with or without corticotherapy.
- •No plans to remove tacrolimus from the patient's immunosuppressive treatment (e.g. no plans to switch to belatacept a priori), during the first 4 years post-transplantation.
- •Affiliation to or beneficiary of a social security scheme
- •Able to read and understand the terms of the protocol
- •Informed consent obtained, including specific consent for genetic analysis of target genes.
- •For women of childbearing potential, presence of effective contraception (already acquired for patients treated with mycophenolic acid as an immunosuppressant).
排除标准
- •Contraindication to the use of tacrolimus
- •Patient already treated with tacrolimus at the time of transplantation
- •Pregnant, parturient or breastfeeding women
- •Patient deprived of liberty by judicial or administrative decision
- •Patient under guardianship or curatorship, or receiving forced psychiatric care
- •Person admitted to a health or social institution
- •Subject cannot be contacted in case of emergency
- •Subject in period of exclusion from another study
研究组 & 干预措施
Tacrolimus once-daily
Patients receiving tacrolimus as a once-daily formulation (Envarsus)
干预措施: Dosage Forms Oral (Drug)
Tacrolimus bid
Patients receiving tacrolimus as a twice-a-day formulation.
干预措施: Dosage Forms Oral (Drug)
结局指标
主要结局
Tacrolimus metabolite concentration
时间窗: month 3
The concentration of tacrolimus metabolites M-I and M-III will be evaluated by liquid chromatography / tandem mass spectrometry (LC-MS/MS) given in micrograms per litre (μg/l).
Genotyping
时间窗: Enrollment
Genotypes of target genes involved in tacrolimus metabolism (CYP450 3A5, CYP450 3A4, ABCB1)
Tacrolimus residual concentration
时间窗: month 3
In addition to the Tacrolimus residual concentration assessed at each visit, this measure will also be performed at T0, T+1h and T+3h for immediate-release tacrolimus and T0, T+1h and T+8h for prolonged-release tacrolimus after treatment. The measurement at T+8h will be carried out on blotting paper with a drop of capillary blood which will be returned by mail, using an envelope given to the patient during the visit. These three measuring points will be used to identify the abbreviated kinetics of tacrolimus during M3 visit.
次要结局
未报告次要终点