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 IC50 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.
Highlights
Tacrolimus (TAC) is an immunosuppressive drug widely prescribed in solid organ transplant patients
therapeutic drug monitoring (TDM) of TAC is mandatory since it was evidenced that lower whole blood concentrations increase risk of acute rejection (ACR) and that some toxicity are induced by high whole blood concentrations [3]
The standard deviation (SD) of the TAC concentrations (C) representing the assay error was calculated by the formula SD = 1+0.1 x C for whole blood concentrations corresponding to an additive and proportional (%) part of the assay error, respectively, and SD = 5+0.12 x C for peripheral blood mononuclear cells (PBMC) concentrations
Summary
Tacrolimus (TAC) is an immunosuppressive drug widely prescribed in solid organ transplant patients. TAC pharmacological response exhibits substantial inter-individual variability This variability can be partially managed by performing therapeutic drug monitoring (TDM) of TAC whole blood concentrations [2]. TDM of TAC is mandatory since it was evidenced that lower whole blood concentrations increase risk of acute rejection (ACR) and that some toxicity are induced by high whole blood concentrations [3]. Despite this personalized approach, some patients experience ACR or toxicity while having blood concentration within the therapeutic range [2]. These observations emphasize the need to look for alternative biomarkers of TAC response
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