Population pharmacokinetics of tacrolimus whole blood and peripheral blood mononuclear cell concentrations in stable kidney-transplanted patients

被引:1
作者
Agergaard, Katrine [1 ,2 ]
Thiesson, Helle C. [2 ]
Carstens, Jan [2 ]
Staatz, Christine E. [3 ]
Jarvinen, Erkka [4 ]
Nielsen, Flemming [4 ]
Christensen, Heidi Dahl [5 ]
Juhl-Sandberg, Rikke [6 ]
Brosen, Kim [4 ]
Stage, Tore Bjerregaard [4 ]
Andersen, Dorte Terp [7 ]
Kjellsson, Maria C. [8 ]
Bergmann, Troels K. [1 ,9 ]
机构
[1] Univ Southern Denmark, Dept Reg Hlth Res, Esbjerg, Denmark
[2] Odense Univ Hosp, Dept Nephrol, Odense, Denmark
[3] Univ Queensland, Sch Pharm, Brisbane, Australia
[4] Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol Pharm & Environm Med, Odense, Denmark
[5] Univ Hosp Southern Denmark, Dept Nephrol, Esbjerg, Denmark
[6] Sygehus Lillebaelt, Med Afdeling, Kolding, Denmark
[7] Univ Hosp Southern Denmark, Dept Clin Mol Biol, Esbjerg, Denmark
[8] Uppsala Univ, Dept Pharm, Pharmacometr Res Grp, Uppsala, Sweden
[9] Odense Univ Hosp, Dept Clin Pharmacol, Odense, Denmark
关键词
immunosuppressants; pharmacogenetics; population pharmacokinetics; therapeutic drug monitoring; transplantation; CLINICAL PHARMACOKINETICS; ABCB1; POLYMORPHISMS; MASS-SPECTROMETRY; CYCLOSPORINE; REJECTION; PHARMACODYNAMICS; QUANTIFICATION; VARIABILITY; VALIDATION; EXPOSURE;
D O I
10.1111/bcp.16277
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
AimTherapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model.MethodsWe prospectively enrolled 63 stable adult kidney-transplanted patients and collected dense (12-h, n = 18) or sparse (4-h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography-mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM.ResultsTacrolimus whole blood concentrations were well described using a two-compartment pharmacokinetic model with a lag-time and first-order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (RC:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non-expressors and NR1I2-25 385T allele expressors demonstrated higher RC:PBMC ratios of 42.4% and 60.7%, respectively.ConclusionTacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies.
引用
收藏
页码:761 / 773
页数:13
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