Non-steady state population kinetics of intravenous phenytoin
Non-steady state population kinetics of intravenous phenytoin
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DOI：
10.1097/00007691-199808000-00010
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发表时间：
1998-08-01
影响因子：
2.5
通讯作者：
Beal, SL
中科院分区：
文献类型：
--
作者：
Frame, B;Beal, SL
本观察性研究探讨了人口统计学、疾病和多种药物对静脉注射苯妥英非稳态人群药代动力学的影响。研究了115名患者。采用混合一阶条件估计的NONMEM程序建立模型。有延迟归纳法的Michaelis-Menten模型优于无归纳法的Michaelis-Menten模型、有即时归纳法的Michaelis-Menten模型和有延迟归纳法的线性模型。当数据拟合Michaelis-Menten延迟诱导模型时，发现体积分布（V-d）依赖于体重和血清白蛋白。假设白蛋白水平为3 g/dl， V-d估计为0.95 l/kg。Michaelis-Menten常数（k(m)）估计为7.9 mg/l。对于体重70公斤的患者，基线最大代谢率为580毫克/天。平均诱导时间为59.5小时。如果在诱导开始后出现发烧，则会增加诱导的程度。该模型在另外26例患者中进行回顾性评估，基于两级反馈的平均预测误差为-0.4 mg/l (-3.0-2.2 mg/l)，平均绝对预测误差为4.7 mg/l （3.2-6.2 mg/l）。鉴于最大代谢率的个体间差异很大，苯妥英水平应经常测量。
This observational study explored the effects of demographics, sickness, and polypharmacy on the non-steady state population pharmacokinetics of intravenous phenytoin. One hundred fifteen patients were studied. Models were developed using the NONMEM program with hybrid first-order conditional estimation. A Michaelis-Menten model with delayed induction was preferred over a Michaelis-Menten model without induction, a Michaelis-Menten model with immediate induction, or a linear model with delayed induction. When the data were fit to a Michaelis-Menten model with delayed induction, the volume of distribution (V-d) was found to depend on weight and serum albumin. The V-d was estimated to be 0.95 l/kg, assuming an albumin level of 3 g/dl. The Michaelis-Menten constant (k(m)) was estimated to be 7.9 mg/l. The baseline maximum metabolic rate was 580 mg/day for a 70-kg patient. The average time to onset of induction was 59.5 hours. If a fever developed after induction began, it increased the extent of induction. This model was evaluated retrospectively in 26 additional patients, yielding a mean prediction error of -0.4 mg/l (-3.0-2.2 mg/l) and a mean absolute prediction error of 4.7 mg/l (3.2-6.2 mg/l) based on two-level feedback. Given the large interindividual variances in maximum metabolic rate, phenytoin levels should be measured frequently.