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

Camille Tron, Jean-Baptiste Woillard, Pauline Houssel-Debry, Véronique David, Caroline Jezequel, Michel Rayar, David Balakirouchenane, Benoit Blanchet, Jean Debord, Antoine Petitcollin, Mickaël Roussel, Marie-Clémence Verdier, Eric Bellissant, Florian Lemaitre, Camille Tron, Jean-Baptiste Woillard, Pauline Houssel-Debry, Véronique David, Caroline Jezequel, Michel Rayar, David Balakirouchenane, Benoit Blanchet, Jean Debord, Antoine Petitcollin, Mickaël Roussel, Marie-Clémence Verdier, Eric Bellissant, Florian Lemaitre

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Model performances-diagnostic plots.
Fig 1. Model performances-diagnostic plots.
Individual predicted versus observed concentrations of tacrolimus in whole blood (A) and in PBMC (B), population predicted versus observed concentrations of tacrolimus in whole blood (C) and in PBMC (D), weighted residuals versus individual predicted concentrations of tacrolimus in whole blood (E) and in PBMC (F).
Fig 2. Relationship between area under the…
Fig 2. Relationship between area under the concentration–time curve from 0 to 12 h (AUC) of tacrolimus in whole blood (WB) and in peripheral mononuclear blood cells (PBMC).
The dotted line is the linear regression curve. (n = 32) (r2 = 0.51, p<0.001).
Fig 3. Influence of recipient ABCB1 1199G>A…
Fig 3. Influence of recipient ABCB1 1199G>A on whole blood and on intracellular (PBMC) areas under the tacrolimus (TAC) concentrations–time curve from 0 to 12 h (AUC).
Each symbol represents mean ± standard deviation of the mean. (n = 29 ABCB1 1199GG, n = 3 ABCB1 1199GA).
Fig 4. Tacrolimus (TAC) pharmacokinetic-pharmacodynamic relationship.
Fig 4. Tacrolimus (TAC) pharmacokinetic-pharmacodynamic relationship.
(A): Relationship between calcineurin maximum inhibition (CaNImax) and TAC maximum concentration (Cmax) in peripheral mononuclear cells (PBMC) or whole blood (WB). Black arrows show tacrolimus concentration inhibiting 37% (IC37) of calcineurin activity (65 pg/million of cells in PBMC and 11 ng/mL in whole blood) and greys arrows show tacrolimus concentration inhibiting 50% (IC50) of calcineurin activity (100 pg/million of cells in PBMC and 18 ng/mL in whole blood). (n = 32). Probability of intracellular target attainement (B). Targets are IC37 and IC50 in PBMC. IC: Inhibitory concentration.

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