Godfrey C, Sweeney K, Miller K, Hamilton R, Kremer J
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, USA.
Br J Clin Pharmacol. 1998 Oct;46(4):369-76. doi: 10.1046/j.1365-2125.1998.t01-1-00790.x.
Methotrexate is considered by many practitioners to be the agent of choice in the treatment of rheumatoid arthritis. The pharmacokinetics of methotrexate have been reported to exhibit significant intersubject variability. Therefore, this study was undertaken to evaluate the population pharmacokinetics of methotrexate during long-term administration in adults with rheumatoid arthritis.
Methotrexate pharmacokinetics were evaluated in a 36 month study of 62 adults with rheumatoid arthritis. Patients received oral or intramuscular doses of methotrexate weekly with pharmacokinetic studies performed every 6 months. Data were analyzed with nonlinear mixed effects modeling.
Three thousand two hundred and sixty post oral or intramuscular dose serum methotrexate concentrations comprising 425 individual concentration vs time profiles were modeled using NONMEM. Covariates that significantly (P < 0.005) influenced the disposition of methotrexate were age (AGE, years), body weight (BW, kg), creatinine clearance (CL(CR), 1 h(-1)), gender (GEN; 0 = male, 1 = female), dose (DOSE, micromol), and fed vs fasted state (FED; 0 = fasted, 1 = fed). The final model describing the biexponential disposition of methotrexate was clearance(CL, 1 h(-1)) = (0.0810BW + 0.257CL(CR))(1-(0.167GEN); central volume (Vc, 1) = 0.311BW; peripheral volume (Vp, 1) = 0.469BW-0.169AGE; intercompartmental clearance (Q, 1 h(-1)) = 4.27(1-0.355GEN); oral absorption rate constant (ka(p.o.), h(-1)) = 4.70-0.0439DOSE*(1-0.507FED); intramuscular absorption rate constant (ka(i.m.), h(-1)) = 0.122DOSE; relative bioavailability (F) = 93.4%; and oral absorption lag time (LAG(p.o.), min) = 13.5. Pharmacokinetic parameters (%CV) for a typical fasted male subject in this study were CL, 7.341 h(-1) (27%); Vc, 23.51 (28%); Vp, 25.31 (31%); Q, 4.25 1 h(-1) (41%); ka(p.o.), 3.67 h(-1) (77%); and ka(i.m.), 3.09 h(-1) (44%).
The population pharmacokinetics of methotrexate in adults with rheumatoid arthritis were well described by this investigation. Substantial interpatient variability was explained by incorporating patient specific data into regression equations predicting pharmacokinetic parameters.
许多从业者认为甲氨蝶呤是治疗类风湿关节炎的首选药物。据报道，甲氨蝶呤的药代动力学存在显著的个体间差异。因此，本研究旨在评估甲氨蝶呤在成年类风湿关节炎患者长期给药期间的群体药代动力学。
在一项为期36个月的研究中，对62名成年类风湿关节炎患者的甲氨蝶呤药代动力学进行了评估。患者每周接受口服或肌肉注射甲氨蝶呤，并每6个月进行一次药代动力学研究。数据采用非线性混合效应模型进行分析。
使用NONMEM对3260次口服或肌肉注射甲氨蝶呤后的血清浓度进行建模，这些浓度包含425个个体浓度与时间的曲线。显著影响甲氨蝶呤处置的协变量（P < 0.005）包括年龄（AGE，岁）、体重（BW，kg）、肌酐清除率（CL(CR)，1 h(-1)）、性别（GEN；0 = 男性，1 = 女性）、剂量（DOSE，微摩尔）以及进食与禁食状态（FED；0 = 禁食，1 = 进食）。描述甲氨蝶呤双指数处置的最终模型为清除率（CL，1 h(-1)） = (0.0810BW + 0.257CL(CR))(1 - (0.167GEN))；中央室容积（Vc，1） = 0.311BW；外周室容积（Vp，1） = 0.469BW - 0.169AGE；室间清除率（Q，1 h(-1)） = 4.27(1 - 0.355GEN)；口服吸收速率常数（ka(p.o.)，h(-)1） = 4.70 - 0.0439DOSE*(1 - 0.507FED)；肌肉注射吸收速率常数（ka(i.m.)，h(-1)） = 0.122DOSE；相对生物利用度（F） = 93.4%；口服吸收滞后时间（LAG(p.o.)，分钟） = 13.5。本研究中典型禁食男性受试者药代动力学参数（%CV）为：CL，7.341 h(-1)（27%）；Vc，23.51（28%）；Vp，25.31（31%）；Q，4.25 1 h(-1)（41%）；ka(p.o.)，3.67 h(-1)（77%）；ka(i.m.)，3.09 h(-1)（44%）。
本研究很好地描述了成年类风湿关节炎患者中甲氨蝶呤的群体药代动力学。通过将患者特定数据纳入预测药代动力学参数的回归方程，解释了患者间的显著差异。
