The CYP3A biomarker 4?-hydroxycholesterol does not improve tacrolimus dose predictions early after kidney transplantation.
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ABSTRACT: 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 (4?OHC) for tacrolimus dose individualization early after kidney transplantation. METHODS:Data were obtained from 79 adult kidney transplant recipients who contributed a total of 625 4?OHC measurements and 1999 tacrolimus whole blood concentrations during the first 2 months after transplantation. The relationships between 4?OHC levels and individual estimates of tacrolimus apparent plasma clearance (CL/Fplasma ) at different time points after transplantation were investigated using scatterplots and population pharmacokinetic modelling. RESULTS:There was no significant correlation between pre-transplant 4?OHC levels and tacrolimus CL/Fplasma the first week (r = 0.19 [95% CI -0.03-0.40]) or between 4?OHC and tacrolimus CL/Fplasma 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 4?OHC was not a statistically significant covariate on tacrolimus CL/Fplasma , neither in terms of absolute values (P = 0.11) nor in terms of changes from baseline (P = 0.17). 4?OHC 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/Fplasma decreased over the same period (median change -13% [IQR -3 to -26%], P < 0.001). CONCLUSIONS:4?OHC does not appear to have a clinical potential to improve individualization of tacrolimus doses early after kidney transplantation.
SUBMITTER: Storset E
PROVIDER: S-EPMC5465334 | biostudies-literature | 2017 Jul
REPOSITORIES: biostudies-literature
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