Elisabet Størset1,2, Kristine Hole3, Karsten Midtvedt1, Stein Bergan4,5, Espen Molden3,4, Anders Åsberg1,4. 1. Department of Transplant Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 2. Institute of Clinical Medicine, University of Oslo, Norway. 3. Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. 4. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway. 5. Department of Pharmacology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
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 4β-hydroxycholesterol (4βOHC) for tacrolimusdose 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/Fplasma ) 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/Fplasma the first week (r = 0.19 [95% CI -0.03-0.40]) or between 4βOHC 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 4βOHC 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). 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/Fplasma 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.
RCT Entities:
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/Fplasma ) 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/Fplasma the first week (r = 0.19 [95% CI -0.03-0.40]) or between 4βOHC 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 4βOHC 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). 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/Fplasma 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.
Authors: N Pallet; A-S Jannot; M El Bahri; I Etienne; M Buchler; B H de Ligny; G Choukroun; C Colosio; A Thierry; C Vigneau; B Moulin; Y Le Meur; A-E Heng; J-F Subra; C Legendre; P Beaune; C Alberti; M A Loriot; E Thervet Journal: Am J Transplant Date: 2015-01-14 Impact factor: 8.086
Authors: R Venkataramanan; A Swaminathan; T Prasad; A Jain; S Zuckerman; V Warty; J McMichael; J Lever; G Burckart; T Starzl Journal: Clin Pharmacokinet Date: 1995-12 Impact factor: 6.447
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