Pharmacogenetic—Whole blood and intracellular pharmacokinetic—Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients

Abstract

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC 50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.

Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients

“…The poor to moderate correlation between [Tac] cells and [Tac] blood after solid organ transplantation has been reported by other research groups 8,11,13–17 . In kidney transplant recipients with a stable kidney function, a moderate correlation between [Tac] cells and [Tac] blood was observed ( r = 0.67), which corresponds to the observation in the present study 11 .…”

“…found an association between ABCB1 1199G>A and [Tac] cells , but not between ABCB1 3435C>T genotypes and [Tac] cells. 17 In a study in 150 liver transplant recipients, Elens et al . found that ABCB1 (1199G>A and 2677G>T/A) genotype significantly influenced hepatic tissue tacrolimus concentrations, whereas the impact of ABCB1 on [Tac] blood was negligible 43 …”

“…8 Moreover, previous studies reported poor to moderate correlations between [Tac] cells and [Tac]blood , indicating that [Tac] blood does not always reflect the concentration at the target site. 8,11,[13][14][15][16][17] This poor correlation may reflect the activity of the efflux transporter protein ABCB1 in mononuclear cell membranes. Differences in ABCB1 activity may result in differences in intralymphocytic tacrolimus accumulation and tacrolimus pharmacodynamics.…”

“…did not find any association between CYP3A4 and CYP3A5 genotype and either [Tac] cells or [Tac] blood. 17 …”

Influence of the Circadian Timing System on Tacrolimus Pharmacokinetics and Pharmacodynamics After Kidney Transplantation

“…The lower C max /C trough ratio, especially after the morning dose, achieved intracellularly compared to whole blood suggests a restricted entrance of Tac molecules inside the cells. It is known that ABCB1 polymorphisms affect the intracellular Tac exposure in PBMCs ( Capron et al, 2010 ; Tron et al, 2020 ). However, no literature has been published to describe the role of circadian rhythms and Pgp on intracellular Tac exposure.…”