de Winter Brenda C M, van Gelder Teun, Glander Petra, Cattaneo Dario, Tedesco-Silva Helio, Neumann Irmgard, Hilbrands Luuk, van Hest Reinier M, Pescovitz Mark D, Budde Klemens, Mathot Ron A A
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands.
Clin Pharmacokinet. 2008;47(12):827-38. doi: 10.2165/0003088-200847120-00007.
The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).
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). A two-compartment model with first-order absorption and elimination was used to describe the data.
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 t(lag) 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).
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.
比较接受霉酚酸酯（MMF）或肠溶霉酚酸钠（EC-MPS）治疗的肾移植患者中霉酚酸（MPA）的药代动力学。
纳入肾移植术后4至257个月接受EC-MPS治疗（n = 208）和MMF治疗（n = 184）患者的MPA浓度-时间曲线。采用非线性混合效应模型（NONMEM）进行群体药代动力学分析。使用具有一级吸收和消除的二室模型来描述数据。
MPA清除率、室间清除率或中央或外周分布容积未检测到差异。各自的值和个体间变异性（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%]。为了充分描述EC-MPS该参数的IIV，对变点参数滞后时间（t(lag)）使用混合模型。服用EC-MPS晨剂量后，分别有51%、32%和17%的人群t(lag)值为0.95、1.88和4.83 h（IIV 8%）。EC-MPS给药后早晨的t(lag)与MMF给药后的t(lag)（0.30 h；p < 0.001 [IIV 11%]）以及EC-MPS evening剂量后的t(lag)（9.04 h；p < 0.001 [IIV 40%]）均有显著差异。事后分析表明，与MMF给药后（中位数0.30 h [0.26 - 0.34 h]；p < 0.001）相比，EC-MPS给药后t(lag)更长且变异性更大（早晨中位数2.0 h [0.9 - 5.5 h]，晚上中位数8.9 h [5.4 - 12.3 h]）。与MMF给药后相比，EC-MPS给药后早晨MPA给药前浓度更高且变异性更大，各自的值分别为2.6 mg/L（0.4 - 24.4 mg/L）和1.6 mg/L（0.2 - 7.6 mg/L）。与MMF治疗的患者（r² = 0.48）相比，EC-MPS治疗的患者给药前浓度与血浆浓度-时间曲线下面积（AUC）之间的相关性更低（r² = 0.02）。
与MMF给药后相比，EC-MPS给药后MPA的吸收延迟且更慢。此外，EC-MPS治疗的患者t(lag)变化更大。在MMF和EC-MPS治疗的患者中，MPA给药前浓度与MPA AUC的相关性均较差。
