Population Pharmacokinetics of Mycophenolic Acid A Comparison between Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Renal Transplant Recipients
Population Pharmacokinetics of Mycophenolic Acid A Comparison between Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Renal Transplant Recipients
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DOI：
10.2165/0003088-200847120-00007
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发表时间：
2008-01-01
影响因子：
4.5
通讯作者：
Mathot, Ron A. A.
中科院分区：
文献类型：
--
作者：
de Winter, Brenda C. M.;van Gelder, Teun;Mathot, Ron A. A.
目的：方法：对208例肾移植患者口服霉酚酸酯（MMF）和184例口服霉酚酸钠肠溶制剂（EC-MPS）后4-257个月的MPA药动学进行比较。使用非线性混合效应模型（NONMEM（R））进行群体药代动力学分析。一个二室模型与一阶吸收和消除被用来描述data.Results：MPA清除率，室间清除率，或中心或外周分布容积检测无差异。相应值和个体间变异性（IIV）分别为16 L/h（39%）、22 L/h（78%）、40 L（100%）和518 L（490%）。EC-MPS的吸收比MMF慢，吸收速率常数分别为3.0 h（-1）和4.1 h（-1）（p < 0.001）[IIV 187%]。将混合模型用于变点参数滞后时间（t（滞后）），以充分描述EC-MPS中该参数的IIV。EC-MPS早晨给药后，51%、32%和17%的人群（IIV 8%）的t（滞后）值分别为0.95、1.88和4.83 h。EC-MPS给药后的早晨t（滞后）与MMF给药后的t（滞后）（0.30 h; p < 0.001 [IIV 11%]）和EC-MPS晚上给药后的t（滞后）（9.04 h; p < 0.001 [IIV 40%]）存在显著差异。事后分析显示，EC-MPS给药后的tlag（早晨中位时间为2.0 h [0.9-5.5 h]，晚上中位时间为8.9 h [5.4-12.3 h]）比MMF给药后（中位时间为0.30 h [0.26-0.34 h]; p < 0.001）更长且变化更大。EC-MPS给药后早晨MPA给药前浓度高于MMF给药后，且变化更大，分别为2.6 mg/L（0.4-24.4 mg/L）和1.6 mg/L（0.2-7.6 mg/L）。EC-MPS组给药前血药浓度与血药浓度-时间曲线下面积（AUC）的相关性（r（2）= 0.02）低于MMF组（r（2）= 0.48）。此外，EC-MPS治疗患者的t（滞后）变化更大。在接受MMF和EC-MPS治疗的患者中，MPA给药前浓度与MPA AUC的相关性较差。
Objective: The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).Methods: MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4-257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM (R)). A two-compartment model with first-order absorption and elimination was used to describe the data.Results: No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L (100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h(-1) and 4.1 h(-1) (p < 0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (t(lag)) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the t(lag) values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. The morning t(lag) following EC-MPS administration was significantly different from both the t(lag) following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the t(lag) following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%]). Post hoc analysis showed that the tlag was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9-5.5 h], evening median 8.9 h [5.4-12.3 h]) than following MMF administration (median 0.30 h [0.26-0.34 h]; p < 0.001). The morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4-24.4 mg/L) and 1.6 mg/L (0.2-7.6 mg/L). The correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r(2) = 0.02) than in MMF-treated patients (r(2) = 0.48).Conclusion: Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the t(lag) varied more in EC-MPS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients.