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

Br J Clin Pharmacol. 2025 Mar;91(3):761-773. doi: 10.1111/bcp.16277. Epub 2024 Oct 10.

Abstract

Aim: Therapeutic 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.

Methods: We 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.

Results: Tacrolimus 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.

Conclusion: Tacrolimus 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.

Keywords: immunosuppressants; pharmacogenetics; population pharmacokinetics; therapeutic drug monitoring; transplantation.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adult
  • Aged
  • Cytochrome P-450 CYP3A / genetics
  • Drug Monitoring / methods
  • Female
  • Genotype
  • Humans
  • Immunosuppressive Agents* / administration & dosage
  • Immunosuppressive Agents* / blood
  • Immunosuppressive Agents* / pharmacokinetics
  • Kidney Transplantation*
  • Leukocytes, Mononuclear* / metabolism
  • Male
  • Middle Aged
  • Models, Biological*
  • Pregnane X Receptor
  • Prospective Studies
  • Tacrolimus* / administration & dosage
  • Tacrolimus* / blood
  • Tacrolimus* / pharmacokinetics

Substances

  • Tacrolimus
  • Immunosuppressive Agents
  • Cytochrome P-450 CYP3A
  • CYP3A5 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ABCB1 protein, human
  • NR1I2 protein, human
  • CYP3A4 protein, human
  • Pregnane X Receptor