Pharmacokinetic Study of Adoport® (Tacrolimus) in Patients With de Novo Kidney Transplantation
Status:
Completed
Trial end date:
2019-07-31
Target enrollment:
Participant gender:
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.