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Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study
Drugs in R&D ( IF 2.2 ) Pub Date : 2020-10-06 , DOI: 10.1007/s40268-020-00319-y
François Riglet 1 , Julie Bertrand 1 , Aurélie Barrail-Tran 2, 3, 4 , Céline Verstuyft 5, 6 , Hugues Michelon 2 , Henri Benech 7 , Antoine Durrbach 8, 9 , Valérie Furlan 10 , Caroline Barau 11
Affiliation  

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.



中文翻译:

来自 CIMTRE 研究的肾移植患者血浆和细胞霉酚酸的群体药代动力学模型

背景与目的

吗替麦考酚酯广泛用于肾移植受者。吗替麦考酚酯被血液酯酶水解为活性药物麦考酚酸 (MPA)。尽管已建议监测 MPA 治疗药物以通过血浆浓度与时间曲线下面积优化治疗效果,但关于外周血单核细胞中 MPA 的浓度知之甚少,其中 MPA 抑制肌苷单磷酸脱氢酶。本研究旨在使用群体方法建立药代动力学模型,以描述 78 名接受霉酚酸酯联合他克莫司和泼尼松治疗的成年肾移植受者血浆和外周血单核细胞中 MPA 的总浓度和未结合浓度。

方法

测定了总的和未结合的血浆浓度和外周血单核细胞浓度。一个三室模型,两个用于血浆 MPA,一个用于外周血单核细胞 MPA,具有零级吸收和一级消除,用于描述数据。

结果

外周血单个核细胞中霉酚酸的平均浓度远高于肌苷单磷酸脱氢酶的半数最大有效浓度,与移植排斥的发生无关。三个协变量影响未结合和细胞内 MPA 的药代动力学:肌酐清除率,对未结合 MPA 清除率有影响,人血清白蛋白,影响未结合 MPA 分数和ABCB1 3435 C>T (rs1045642) 遗传多态性,对 MPA 流出有影响由外周血单个核细胞转运。

结论

这种群体药代动力学模型证明了 MPA 的细胞内积累,MPA 流出细胞依赖于 P-糖蛋白转运蛋白。然而,需要进一步研究来调查外周血单核细胞中 MPA 浓度与给药方案优化的相关性。

更新日期:2020-10-07
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