Prémaud Aurélie, Debord Jean, Rousseau Annick, Le Meur Yannick, Toupance Olivier, Lebranchu Yvon, Hoizey Guillaume, Le Guellec Chantal, Marquet Pierre
Department of Pharmacology-Toxicology, University Hospital, 2 Avenue Martin-Luther-King, 87042 Limoges, France.
Clin Pharmacokinet. 2005;44(8):837-47. doi: 10.2165/00003088-200544080-00005.
Mycophenolic acid (MPA) shows complex plasma concentration-time profiles, particularly in the immediate (first month) post-transplantation phase for which no relevant pharmacokinetic model has been proposed thus far.
The aim of this study was to develop a model to accurately describe the time profile of plasma MPA concentrations after oral administration of mycophenolate mofetil in adult kidney transplant patients, in any post-transplantation period.
Full interdose pharmacokinetic profiles were collected in 45 adult renal transplant patients who were orally administered mycophenolate mofetil and ciclosporin; 25 patients were de novo transplant patients for whom individual pharmacokinetics were assessed at three post-transplantation periods (days 3, 7 and 30) and 20 patients were stable transplant patients (>3 months post-transplantation). MPA was determined in plasma by liquid chromatography-mass spectrometry. Models combining a single- or double-input (described as single or double gamma distributions) with one- or two-compartments were developed using in-house software and fitted to the individual profiles by nonlinear regression.
Visual inspection of the pharmacokinetic profiles showed highly variable absorption profiles and secondary peaks of various intensity. The pharmacokinetic models including a double gamma distribution best fitted these various profiles in the immediate post-transplantation period (mean bias and precision of -0.92% and 20.19%; -1.5% and 18.02%, on day 7 and day 30, respectively), while in the stable post-grafting phase (beyond 3 months), the single- and double-absorption models performed similarly (mean bias and precision of -3.37% and 17.64%; -3.12% and 18.44%, on day 7 and day 30, respectively).
The proposed pharmacokinetic models adequately describe the concentration-time profiles of MPA in renal transplant patients and could be helpful in the development of tools for MPA monitoring.
霉酚酸（MPA）呈现出复杂的血药浓度-时间曲线，尤其是在移植后即刻（第一个月）阶段，目前尚未有相关的药代动力学模型。
本研究旨在建立一个模型，以准确描述成年肾移植患者在移植后任何时期口服霉酚酸酯后血浆MPA浓度的时间曲线。
收集了45例口服霉酚酸酯和环孢素的成年肾移植患者的完整服药间期药代动力学曲线；25例为初次移植患者，在移植后的三个时期（第3天、第7天和第30天）评估个体药代动力学，20例为稳定移植患者（移植后>3个月）。采用液相色谱-质谱法测定血浆中的MPA。使用内部软件开发了将单输入或双输入（描述为单伽马分布或双伽马分布）与单室或双室相结合的模型，并通过非线性回归将其拟合到个体曲线。
药代动力学曲线的直观检查显示吸收曲线高度可变且有不同强度的次级峰。包括双伽马分布的药代动力学模型在移植后即刻阶段最能拟合这些不同的曲线（第7天和第30天的平均偏差和精密度分别为-0.92%和20.19%；-1.5%和18.02%），而在移植后稳定期（超过3个月），单吸收和双吸收模型表现相似（第7天和第30天的平均偏差和精密度分别为-3.37%和17.64%；-3.12%和18.44%）。
所提出的药代动力学模型能够充分描述肾移植患者中MPA的浓度-时间曲线，有助于开发MPA监测工具。
