Journal
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Volume 83, Issue 7, Pages 1457-1465Publisher
WILEY
DOI: 10.1111/bcp.13248
Keywords
4-beta hydroxycholesterol; kidney transplantation; population pharmacokinetics; tacrolimus
Categories
Funding
- South-Eastern Norway Regional Health Authority
Ask authors/readers for more resources
AIMS Tacrolimus is a cornerstone in modern immunosuppressive therapy after kidney transplantation. Tacrolimus dosing is challenged by considerable pharmacokinetic variability, both between patients and over time after transplantation, partly due to variability in cytochrome P450 3A (CYP3A) activity. The aim of this study was to assess the value of the endogenous CYP3A marker 4-hydroxycholesterol (4OHC) for tacrolimus dose individualization early after kidney transplantation. METHODS Data were obtained from 79 adult kidney transplant recipients who contributed a total of 625 4OHC measurements and 1999 tacrolimus whole blood concentrations during the first 2 months after transplantation. The relationships between 4OHC levels and individual estimates of tacrolimus apparent plasma clearance (CL/F-plasma) at different time points after transplantation were investigated using scatterplots and population pharmacokinetic modelling. RESULTS There was no significant correlation between pre-transplant 4OHC levels and tacrolimus CL/F-plasma the first week (r=0.19 [95% CI -0.03-0.40]) or between 4OHC and tacrolimus CL/F-plasma 1 week (r=0.20 [-0.11-0.47]), 4 weeks (r=0.21 [-0.07-0.46]) or 2 months (r=0.24 [-0.03-0.48]) after transplantation (P0.06). In the population analysis, time-varying 4OHC was not a statistically significant covariate on tacrolimus CL/F-plasma, neither in terms of absolute values (P=0.11) nor in terms of changes from baseline (P=0.17). 4OHC values increased between 1 week and 2 months after transplantation (median change +57% [IQR +22-83%], P<0.001), indicating increasing CYP3A activity. Contradictorily, tacrolimus CL/F-plasma decreased over the same period (median change -13% [IQR -3 to -26%], P<0.001). CONCLUSIONS 4OHC does not appear to have a clinical potential to improve individualization of tacrolimus doses early after kidney transplantation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available