Clinical trial NCT03076151: Pharmacokinetic Study of Adoport® (Tacrolimus) in Patients With de Novo Kidney Transplantation
Official title: Interventional Multicentre Pharmacokinetic Study of Adoport® (Tacrolimus) in Patients With de Novo Kidney Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Transplantation
Kidney
Pharmacokinetic
Keywords: Transplantation
Kidney
pharmacokinetic
bayesian estimators
Lead sponsor: University Hospital, Limoges
Sponsor class: OTHER
First posted: 2017-03-10
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: Tacrolimus is a calcineurin inhibitor widely used for the prevention of allograft rejection in solid organ and bone marrow transplantation. It is characterized by a narrow therapeutic index and large inter-individual pharmacokinetic variability. Adoport® is an immediate-release formulation of tacrolimus, to be administered twice daily. Because of a narrow therapeutic window and a better correlation between pre-dose level and effects than between dose and effect, therapeutic drug monitoring (TDM) based on trough whole blood tacrolimus concentrations is recommended for Adoport®. TDM helps to minimize the risk of acute rejection and the occurrence of adverse effects (mainly nephrotoxicity and, to a lesser extent, neurotoxicity).

As reported in a consensus document from a consortium of European experts on tacrolimus TDM, the interdose area-under-the curve (AUC0-12h) is expected to be the best marker of tacrolimus exposure. However, tacrolimus monitoring based on full AUC0-12h is difficult to set up in routine, due to clinical constraints and the necessity of multiple samples. Calculation of the AUC0-12h using Bayesian estimation and a limited sampling strategy, i.e. a few blood samples collected during the early phase post-dose would represent an elegant solution, as already done for other tacrolimus formulations.

Furthermore, the pharmacokinetics (PK) of tacrolimus is influenced by a single nucleotide polymorphism within intron 3 of cytochrome P450 3A5 (CYP3A5). Patients who carry at least one CYP3A5\*1 allele are considered to be CYP3A5 expressors (about 12% of the Caucasian population, Hapmap project) and thus require a 1.5 to 2-fold higher starting dose than CYP3A5\*3/\*3 carriers to reach the predefined target exposure early after transplantation. Although this polymorphism showed no impact on the performance of the Bayesian estimators previously developed for other tacrolimus formulation, the patient status for CYP3A5\*3 will be considered in this pharmacokinetic study as a potential covariate in, or confounding factor of, the PK model. Specifically, owing to a 12% frequency in the White European population, about 4 patients carriers of the CYP3A5\*1 allele are expected in this study; the performance of the PK model and Bayesian estimator developed will be specifically evaluated in this subgroup.


Eligibility criteria: Inclusion Criteria:

1. Subject's written informed consent of the study
2. Male and female (\>= 18 years)
3. Recipients of a first kidney allograft
4. Patients transplanted for less than 7 days at enrolment
5. Patients affiliated to a social security system

Exclusion Criteria:

1. Patients presenting any contraindication to tacrolimus according to the summary of product characteristics of Adoport®
2. Patient presenting anti-HLA antibodies against the graft in pre-transplantation (DSA)
3. Recipients of any transplanted organ other than the kidney
4. Pregnant (positive BHCG test) or lactating women
5. Women without any method of contraception, except for women with no childbearing potential (according to the guidelines of the working group, Clinical Trial Facilitation Group, related to contraception and pregnancy test in clinical trials)
6. Patients participating in any other interventional clinical study at inclusion as well as during the whole course of the current study
7. Patient under judicial protection
8. Patients incapable of understanding the purposes and risks of the study, who cannot give written informed consent, or who are unwilling to comply with the study protocol

Primary outcomes:
measure: Tacrolimus bayesian estimator performance
timeFrame: Month 3
Secondary outcomes:
measure: Tacrolimus concentrations predicted by the PK model using a limited sample strategy
timeFrame: Month 3
Other outcomes:
Locations:
city: Amiens
country: France
facility: Amiens Picardie University Hospital
city: Limoges
country: France
facility: Limoges University Hospital
city: Poitiers
country: France
facility: Poitiers University Hospital
city: Rouen
country: France
facility: CHU de ROUEN
city: Tours
country: France
facility: Tours University Hospital
Study officials:
affiliation: University Hospital, Limoges
name: Pierre Marquet, MD
role: PRINCIPAL_INVESTIGATOR
References: