Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study

Abstract Background and Objective Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy...

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Autores principales:	François Riglet, Julie Bertrand, Aurélie Barrail-Tran, Céline Verstuyft, Hugues Michelon, Henri Benech, Antoine Durrbach, Valérie Furlan, Caroline Barau
Formato:	article
Lenguaje:	EN
Publicado:	Adis, Springer Healthcare 2020
Materias:	Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/aebc7369cc8943ce95212329c4a83a17
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spelling	oai:doaj.org-article:aebc7369cc8943ce95212329c4a83a172021-12-02T18:37:13ZPopulation Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study10.1007/s40268-020-00319-y1174-58861179-6901https://doaj.org/article/aebc7369cc8943ce95212329c4a83a172020-10-01T00:00:00Zhttps://doi.org/10.1007/s40268-020-00319-yhttps://doaj.org/toc/1174-5886https://doaj.org/toc/1179-6901Abstract Background and Objective Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. Methods Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. Results Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and the ABCB1 3435 C>T (rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. Conclusion This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation.François RigletJulie BertrandAurélie Barrail-TranCéline VerstuyftHugues MichelonHenri BenechAntoine DurrbachValérie FurlanCaroline BarauAdis, Springer HealthcarearticleTherapeutics. PharmacologyRM1-950ENDrugs in R&D, Vol 20, Iss 4, Pp 331-342 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 François Riglet Julie Bertrand Aurélie Barrail-Tran Céline Verstuyft Hugues Michelon Henri Benech Antoine Durrbach Valérie Furlan Caroline Barau Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study
description	Abstract Background and Objective Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. Methods Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. Results Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and the ABCB1 3435 C>T (rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. Conclusion This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation.
format	article
author	François Riglet Julie Bertrand Aurélie Barrail-Tran Céline Verstuyft Hugues Michelon Henri Benech Antoine Durrbach Valérie Furlan Caroline Barau
author_facet	François Riglet Julie Bertrand Aurélie Barrail-Tran Céline Verstuyft Hugues Michelon Henri Benech Antoine Durrbach Valérie Furlan Caroline Barau
author_sort	François Riglet
title	Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study
title_short	Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study
title_full	Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study
title_fullStr	Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study
title_full_unstemmed	Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study
title_sort	population pharmacokinetic model of plasma and cellular mycophenolic acid in kidney transplant patients from the cimtre study
publisher	Adis, Springer Healthcare
publishDate	2020
url	https://doaj.org/article/aebc7369cc8943ce95212329c4a83a17
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Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study

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