College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Korea.
Clin Ther. 2012 Aug;34(8):1816-26. doi: 10.1016/j.clinthera.2012.06.022. Epub 2012 Jul 13.
Methotrexate (MTX) is often used to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, MTX has great pharmacokinetic variability and its use can result in fatal complications and/or infections after HSCT.
The purposes of this study were to build a population pharmacokinetic model of MTX treatment in Korean patients who have undergone HSCT and to identify covariates, including genetic polymorphisms, that affect the pharmacokinetic properties of MTX.
Clinical characteristics and MTX concentration data for 20 post-HSCT patients were collected. For each patient, ABCB1, ABCC2, ATIC, GGH, MTHFR, and TYMS genotyping was performed. Population pharmacokinetic analysis was performed using the NONMEM program. Analysis of MTX pharmacokinetic properties was accomplished using a 2-compartment pharmacokinetic model that incorporated first-order conditional estimation methods with interaction. The effects of a variety of demographic and genetic factors on MTX disposition were investigated.
The study population consisted of 12 men (60%) and 8 women (40%). Median age and body weight were 28 years (range, 18-49 years) and 55.6 kg (range, 44.8-80.8 kg), respectively. Within the study population, the estimated mean MTX clearance (CL) was 7.08 L/h, whereas the mean central compartment volume (V(1)) of MTX distribution was 19.4 L. MTX CL was significantly affected by glomerular filtration rate (GFR), penicillin use, and the ABCB1 3435 genotype. Interindividual variabilities for CL and V(1) were 21.6% and 73.3%. A 10-mL/min GFR increase was associated with a 32% increase in mean MTX CL, whereas penicillin use was associated with a decrease in MTX CL of 61%. MTX CL was significantly greater (by ∼21%) in patients with the ABCB1 3435 CC and CT genotype than in those with the ABCB1 3435 TT genotype (P < 0.001).
There was great interindividual variation in MTX pharmacokinetic properties in patients who had undergone HSCT. GFR, concurrent penicillin use, and the presence of the ABCB1 3435 C<T genotypes significantly affected MTX CL. The MTX population pharmacokinetic model developed here may provide useful information for individualizing MTX therapy after HSCT.
甲氨蝶呤（MTX）常用于预防异基因造血干细胞移植（HSCT）后的移植物抗宿主病（GVHD）。然而，MTX 具有很大的药代动力学变异性，其使用会导致 HSCT 后发生致命并发症和/或感染。
本研究旨在建立一个韩国 HSCT 患者 MTX 治疗的群体药代动力学模型，并确定包括遗传多态性在内的影响 MTX 药代动力学特性的协变量。
收集了 20 名 HSCT 后患者的临床特征和 MTX 浓度数据。对每位患者进行 ABCB1、ABCC2、ATIC、GGH、MTHFR 和 TYMS 基因分型。使用 NONMEM 程序进行群体药代动力学分析。采用包含一级条件估计方法和相互作用的 2 室药代动力学模型分析 MTX 的药代动力学特性。研究了各种人口统计学和遗传因素对 MTX 分布的影响。
研究人群包括 12 名男性（60%）和 8 名女性（40%）。中位年龄和体重分别为 28 岁（范围 18-49 岁）和 55.6kg（范围 44.8-80.8kg）。在研究人群中，MTX 清除率（CL）的估计平均值为 7.08L/h，而 MTX 分布的中央室容积（V1）的平均值为 19.4L。MTX CL 受肾小球滤过率（GFR）、青霉素使用和 ABCB1 3435 基因型显著影响。CL 和 V1 的个体间变异性分别为 21.6%和 73.3%。GFR 增加 10mL/min，MTX CL 平均增加 32%，而青霉素使用使 MTX CL 降低 61%。与 ABCB1 3435 TT 基因型相比，ABCB1 3435 CC 和 CT 基因型患者的 MTX CL 显著增加（约 21%）（P<0.001）。
HSCT 患者 MTX 药代动力学特性存在较大个体间差异。GFR、同时使用青霉素和 ABCB1 3435 C>T 基因型显著影响 MTX CL。本研究建立的 MTX 群体药代动力学模型可为 HSCT 后 MTX 个体化治疗提供有用信息。
