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The CYP3A biomarker 4β‐hydroxycholesterol does not improve tacrolimus dose predictions early after kidney transplantation
Author(s) -
Størset Elisabet,
Hole Kristine,
Midtvedt Karsten,
Bergan Stein,
Molden Espen,
Åsberg Anders
Publication year - 2017
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13248
Subject(s) - tacrolimus , transplantation , kidney transplantation , population , medicine , pharmacokinetics , urology , cyp3a , cyp3a5 , biomarker , pharmacology , chemistry , cytochrome p450 , biochemistry , environmental health , metabolism , genotype , gene
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 4β‐hydroxycholesterol (4βOHC) for tacrolimus dose individualization early after kidney transplantation. Methods Data were obtained from 79 adult kidney transplant recipients who contributed a total of 625 4βOHC measurements and 1999 tacrolimus whole blood concentrations during the first 2 months after transplantation. The relationships between 4βOHC 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 4βOHC levels and tacrolimus CL/F plasma the first week ( r = 0.19 [95% CI −0.03‐0.40]) or between 4βOHC 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 ( P ≥ 0.06). In the population analysis, time‐varying 4βOHC 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). 4βOHC 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 4βOHC does not appear to have a clinical potential to improve individualization of tacrolimus doses early after kidney transplantation.