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

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

PloS one, 2020-03, Vol.15 (3), p.e0230195 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients
Autor: Tron, Camille ; Woillard, Jean-Baptiste ; Houssel-Debry, Pauline ; David, Véronique ; Jezequel, Caroline ; Rayar, Michel ; Balakirouchenane, David ; Blanchet, Benoit ; Debord, Jean ; Petitcollin, Antoine ; Roussel, Mickaël ; Verdier, Marie-Clémence ; Bellissant, Eric ; Lemaitre, Florian
Chatenoud, Lucienne
Assuntos: Analysis ; Biological markers ; Biology and Life Sciences ; Biomarkers ; Blood ; Blood levels ; Calcineurin ; Cytochrome P-450 ; Deoxyribonucleic acid ; DNA ; EDTA ; Enzymes ; Ethylenediaminetetraacetic acid ; Everolimus ; Exposure ; Genetic polymorphisms ; Genotypes ; Glycoproteins ; Human health and pathology ; Hépatology and Gastroenterology ; Immunosuppressive agents ; Immunotherapy ; Intracellular ; Leukocytes (mononuclear) ; Life Sciences ; Liver ; Liver transplantation ; Liver transplants ; Lymphocytes ; Medicine and Health Sciences ; Organ transplant recipients ; Organ transplantation ; Peripheral blood mononuclear cells ; Pharmaceutical sciences ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Polymorphism ; Precision medicine ; Standard deviation ; Surgery ; Tacrolimus ; Therapy ; Toxicology ; Transplantation ; Transplants & implants
É parte de: PloS one, 2020-03, Vol.15 (3), p.e0230195
Notas: PMCID: PMC7067455
Competing Interests: The authors have declared that no competing interests exist.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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

United States: Public Library of Science

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