A population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients
2019
AIMS
The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to
develop a clinical tool for selecting the best starting dose for each patient.
METHODS
Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic
analysis was conducted using nonlinear mixed-effects modelling. Demographic, clinical and genetic parameters were evaluated
as covariates.
RESULTS
A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described
using a two-compartment model. The mean absorption rate was 3.6 h1
, clearance was 23.0 l h–1 (39% interindividual variability,
IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion
variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin
and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance
(80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to
individualize the tacrolimus starting dose: Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added
value of the starting dose model.
CONCLUSIONS
For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These
covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on
these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.
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