Skip to Main content Skip to Navigation
Journal articles

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 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 theABCB1 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.
Document type :
Journal articles
Complete list of metadata

https://hal.inrae.fr/hal-03209277
Contributor : Christopher Lallemant <>
Submitted on : Tuesday, May 11, 2021 - 5:20:53 PM
Last modification on : Saturday, July 3, 2021 - 12:29:17 AM

File

2020_Riglet_Drugs in R&D.pdf
Files produced by the author(s)

Identifiers

Citation

François Riglet, Julie Bertrand, Aurélie Barrail-Tran, Céline Verstuyft, Hugues Michelon, et al.. Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study. Drugs in R&D, Springer Verlag, 2020, 20 (4), pp.331-342. ⟨10.1007/s40268-020-00319-y⟩. ⟨hal-03209277⟩

Share

Metrics

Record views

112

Files downloads

154