Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
Br J Clin Pharmacol. 2013 Feb;75(2):463-75. doi: 10.1111/j.1365-2125.2012.04372.x.
To evaluate pharmacogenetic factors as contributors to the variability of unbound mycophenolic acid (MPA) exposure in adult allogeneic haematopoietic cell transplantation (alloHCT) recipients.
A population-based pharmacokinetic (PK) model of unbound MPA was developed using non-linear mixed-effects modelling (nonmem). Previously collected intensive unbound MPA PK data from 132 adult alloHCT recipients after oral and intravenous dosing of the prodrug mycophenolate mofetil (MMF) were used. In addition to clinical covariates, genetic polymorphisms in UGT1A8, UGT1A9, UGT2B7 and MRP2 were evaluated for their impact on unbound MPA PK.
Unbound MPA concentration-time data were well described by a two compartment model with first order absorption and linear elimination. For the typical patient (52 years of age, creatinine clearance 86 ml min(-1)), the median estimated values [coefficient of variation, %, (CV)] of systemic clearance, intercompartmental clearance, central and peripheral volumes of MPA were 1610 l h(-1) (37.4%), 541 l h(-1) (75.6%), 1230 l (37.5%), and 6140 l (120%), respectively. After oral dosing, bioavailability was low (0.56) and highly variable (CV 46%). No genetic polymorphisms tested significantly explained the variability among individuals. Creatinine clearance was a small but significant predictor of unbound MPA CL. No other clinical covariates impacted unbound MPA PK.
In adult alloHCT recipients, variability in unbound MPA AUC was large and remained largely unexplained even with the inclusion of pharmacogenetic information. Targeting unbound MPA AUC in a patient will require therapeutic drug monitoring.
评估遗传因素对成年异基因造血细胞移植（alloHCT）受者中游离麦考酚酸（MPA）暴露变异性的影响。
采用非线性混合效应模型（nonmem）建立游离 MPA 的基于人群的药代动力学（PK）模型。使用先前从 132 例成年 alloHCT 受者中收集的口服和静脉给予麦考酚酸酯前药吗替麦考酚酯（MMF）后的密集游离 MPA PK 数据。除临床协变量外，还评估了 UGT1A8、UGT1A9、UGT2B7 和 MRP2 的遗传多态性对游离 MPA PK 的影响。
游离 MPA 浓度-时间数据通过具有一级吸收和线性消除的两室模型得到很好的描述。对于典型患者（52 岁，肌酐清除率 86 ml min(-1)），系统清除率、隔室间清除率、MPA 的中央和外周体积的中位估计值[变异系数，%（CV）]分别为 1610 l h(-1)（37.4%）、541 l h(-1)（75.6%）、1230 l（37.5%）和 6140 l（120%）。口服给药后，生物利用度低（0.56）且高度可变（CV 46%）。未测试的遗传多态性显著解释个体间的变异性。肌酐清除率是游离 MPA CL 的一个小但显著的预测因子。其他临床协变量对游离 MPA PK 没有影响。
在成年 alloHCT 受者中，游离 MPA AUC 的变异性很大，即使包括遗传药理学信息，也仍有很大一部分无法解释。在患者中靶向游离 MPA AUC 需要治疗药物监测。
