Population pharmacokinetics of tacrolimus in children with nephrotic syndrome

Abstract

Aims: Nephrotic syndrome (NS) is the most common clinical manifestation of glomerular disease in children. Currently, tacrolimus (TAC) is widely used in children with NS. However, pharmacokinetic data in children with nephrotic syndrome is limited. This study was intended to evaluate the population pharmacokinetics (PPK) of TAC in paediatric NS and to optimize dosing regimen.

Methods: Blood samples from NS children treated with TAC were collected and the blood concentrations of TAC were detected using HPLC-MS/MS. A PPK model was developed using NONMEM software. Pharmacogenetic analysis was carried out in the CYP3A5 gene.

Results: The data from 28 children were used for PPK analysis. A one-compartment model and first-order elimination were accorded with the TAC data in paediatric NS. A covariate analysis showed that body weight and CYP3A5 genotype significantly affected TAC pharmacokinetics. Monte Carlo simulation indicated that NS children with CYP3A5*3/*3 receiving 0.10 mg kg-1 dose-1 twice daily and NS children with CYP3A5*1 receiving 0.25 mg kg-1 dose-1 twice daily TAC could achieve the target concentrations of 5-10 ng ml-1 .

Conclusion: The PPK of TAC was estimated in children with NS and a CYP3A5 genotype-based dosing regimen was set up based on simulations.

Keywords: children; nephrotic syndrome; pharmacokinetics; tacrolimus.

© 2018 The British Pharmacological Society.

Figures

Figure 1

The concentration vs. time profile

Figure 2

Diagnostic goodness‐of‐fit plots for the final population pharmacokinetic model of tacrolimus, including (A) observed (DV) vs. population prediction (PRED); (B) DV vs. individual prediction (IPRED); (C) time vs. conditional weighted residuals (CWRES); and (D) PRED vs. CWRES

Figure 3

Normalized prediction distribution errors (NPDE) analysis for the tacrolimus final model. NPDE: QQ‐plot of the distribution of the NPDE versus the theoretical N(0,1) distribution (left). Histogram of the distribution of the NPDE, with the density of the standard Gaussian distribution overlaid (right)

Figure 4

Simulation of the median for tacrolimus steady state C0 obtained in patients of two genetic backgrounds