The CYP3A biomarker 4β-hydroxycholesterol does not improve tacrolimus dose predictions early after kidney transplantation.
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.



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.



There was no significant correlation between pre-transplant 4βOHC levels and tacrolimus CL/Fplasmathe first week (r = 0.19 [95% CI -0.03-0.40]) or between 4βOHC and tacrolimus CL/Fplasma1 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/Fplasmadecreased over the same period (median change -13% [IQR -3 to -26%], P < 0.001).



4βOHC does not appear to have a clinical potential to improve individualization of tacrolimus doses early after kidney transplantation.
Department of Transplant Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.
Elisabet
E
Størset
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
Kristine
K
Hole
Department of Transplant Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Karsten
K
Midtvedt
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.|Department of Pharmacology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Stein
S
Bergan
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.|Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
Espen
E
Molden
Department of Transplant Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
Anders
0000-0002-0628-1769
A
Åsberg
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D057234:Preoperative Period; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use
D015415:Biomarkers; D006888:Hydroxycholesterols; D007166:Immunosuppressive Agents; C099828:cholest-5-ene-3,4-diol; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
4β-hydroxycholesterol; kidney transplantation; population pharmacokinetics; tacrolimus