Filler Guido, Bendrick-Peart Jamie, Christians Uwe
Department of Paediatrics, Children's Hospital at London Health Science Centre, University of Western Ontario, London, Ontario, Canada.
Ther Drug Monit. 2008 Apr;30(2):138-42. doi: 10.1097/FTD.0b013e31816ba73a.
This review summarizes the pharmacokinetics in children and youths of 2 commonly used immunosuppressive drugs, mycophenolate mofetil (MMF) and sirolimus (Sir), as presented at the IATDMCT 2007 conference. The review focuses on the developmental changes of drug disposition during childhood and adolescence. Regarding mycophenolate mofetil, the authors were unable to demonstrate age dependency of MMF in combination with cyclosporine. By contrast, there was an inverse relationship between age and the dose-normalized mycophenolate (MPA) area-under-the-time-concentration curve (AUC) in children who received concomitant tacrolimus (Tac). Dose-normalized MPA AUCs were higher than commonly observed in adult patients. It can be hypothesized that the age dependency is related to developmental changes in the expression of the UDP-glucuronosyltransferases. Sirolimus half-life and mean residence time (MRT) are shorter than in adults. Similar to that in adults, there is a profound drug-drug interaction between cyclosporine and Sir. In our own experience, Sir was started at 0.13 +/- 0.05 mg/kg/day. The average Sir AUC was 64.9 +/- 29.7 ngh/mL. The median (range) AUC for each metabolite was as follows: 12-hydroxy-Sir, 7.6 (0.2-18.8); 46-hydroxy-Sir, 3.1 (0.0-12.4); 24-hydroxy-Sir, 4.3 (0.0-12.6); piperidine-hydroxy-Sir, 3.5 (0.0-8.3); 39-desmethyl-Sir, 3.6 (0.0-11.3); 16-desmethyl-Sir, 5.0 (0.1-9.9); and di-hydroxy-Sir, 4.3 (0.0-32.5) ngh/mL. Of the total metabolite AUC, 77.5% was due to hydroxylated metabolites, while 39-O-desmethyl Sir (the main metabolite in adults) comprised only 8.4% of the metabolites. This is clinically relevant, as 39-O-desmethyl Sir shows 86% to 127% cross-reactivity with the Sir immunoassay. Metabolites reached a median AUC of 60% of that of Sir, but the range was 2.6% to 136%. The age dependency of Sir metabolite formation was confirmed in a human liver microsome model. On the basis of the age dependency of piperidine-hydroxy Sir, the authors postulate that the ontogeny of the drug disposition can be largely explained by developmental changes of the CYP2C8 expression. In conclusion, both Sir and MMF drug disposition vary in children and adolescents from adult patients, most likely because of developmental changes of biliary transporters and metabolic enzymes.
本综述总结了在2007年国际儿科移植和透析大会上所展示的两种常用免疫抑制药物——吗替麦考酚酯（MMF）和西罗莫司（Sir）在儿童和青少年中的药代动力学情况。该综述着重关注儿童期和青春期药物处置的发育变化。关于吗替麦考酚酯，作者未能证明MMF与环孢素联合使用时存在年龄依赖性。相比之下，在接受他克莫司（Tac）的儿童中，年龄与剂量标准化的霉酚酸（MPA）时间-浓度曲线下面积（AUC）呈负相关。剂量标准化的MPA AUC高于成年患者中常见的值。可以推测，年龄依赖性与尿苷二磷酸葡萄糖醛酸转移酶表达的发育变化有关。西罗莫司的半衰期和平均驻留时间（MRT）比成年人短。与成年人相似，环孢素和Sir之间存在显著的药物相互作用。根据我们自己的经验，Sir起始剂量为0.13±0.05mg/kg/天。Sir的平均AUC为64.9±29.7ngh/mL。每种代谢物的中位数（范围）AUC如下：12-羟基-Sir，7.6（0.2-18.8）；46-羟基-Sir，3.1（0.0-12.4）；24-羟基-Sir，4.3（0.0-12.6）；哌啶-羟基-Sir，3.5（0.0-8.3）；39-去甲基-Sir，3.6（0.0-11.3）；16-去甲基-Sir，5.0（0.1-9.9）；二羟基-Sir，4.3（0.0-32.5）ngh/mL。在总代谢物AUC中，77.5%归因于羟基化代谢物，而39-O-去甲基Sir（成年人中的主要代谢物）仅占代谢物的8.4%。这在临床上具有相关性，因为39-O-去甲基Sir与Sir免疫测定显示出86%至127%的交叉反应性。代谢物的中位数AUC达到Sir的60%，但范围为2.6%至136%。在人肝微粒体模型中证实了Sir代谢物形成的年龄依赖性。基于哌啶-羟基Sir的年龄依赖性，作者推测药物处置的个体发生在很大程度上可以由CYP2C8表达 的发育变化来解释。总之，Sir和MMF的药物处置在儿童和青少年与成年患者中有所不同，最可能的原因是胆汁转运体和代谢酶的发育变化。
