Use of adaptive control with feedback to individualize suramin dosing.
Use of adaptive control with feedback to individualize suramin dosing.
复制标题
DOI：
--
复制
发表时间：
1992
期刊：
影响因子：
11.2
通讯作者：
H. Scher;D. Jodrell;J. Iversen;T. Curley;W. Tong;M. Egorin;A. Forrest
中科院分区：
文献类型：
--
作者：
H. Scher;D. Jodrell;J. Iversen;T. Curley;W. Tong;M. Egorin;A. Forrest
苏拉明是第一个公认的生长因子抑制剂，在临床试验中已证明抗肿瘤活性。苏拉明的给药因治疗指数狭窄和测定的药代动力学参数的显著患者间变异性而变得复杂。由于抗肿瘤反应和剂量限制性毒性均与血浆苏拉明浓度曲线相关，因此需要个体化给药方案以实现化合物的最佳给药。在这份报告中，使用最佳采样理论，以获得稀疏的数据监测和控制策略与苏拉明使用。7例患者采用固定速率连续输注方案，达到峰浓度（280-300 μ g/ml）的时间范围为7.7-21天（平均13.2天），在3-22天（平均11天）内下降至150 μ g/ml。使用最大似然算法拟合初始群体药代动力学模型。中央室的平均容积为4.5 +/- 6.7 L/m2，外周室的容积为10.6 +/- 1.4 L/m2，分布半衰期为25 +/- 5.4 h，消除半衰期为29.7 +/- 6.9 h。终末半衰期短于先前报告的。这些参数用作迭代2阶段分析的初始群体模型。得到的分布半衰期为22.3 +/- 2.7 h，消除半衰期为28.2 +/- 5.0 h，两者相似，反映了密集采样。然后使用迭代2阶段分析模型确定最佳采样时间，并模拟旨在将血浆浓度维持在规定浓度范围内的方案的20个数据集。该策略目前正在I期临床试验中进行研究。
Suramin is the first putative growth factor inhibitor in clinical trial that has demonstrated antitumor activity. Administration of suramin is complicated by a narrow therapeutic index and significant interpatient variability of measured pharmacokinetic parameters. Because both antitumor response and dose-limiting toxicities are related to plasma suramin concentration profiles, individualized dose schedules are required for optimal administration of the compound. In this report, the use of optimal sampling theory to derive sparse data monitoring and control strategies for use with suramin is described. A fixed rate continuous infusion schedule was used in seven patients, and the time to peak concentration (280-300 micrograms/ml) ranged from 7.7-21 days (mean, 13.2 days) with a decline to 150 micrograms/ml in 3-22 days (mean, 11 days). An initial population pharmacokinetic model was fit using a maximum likelihood algorithm. The mean volume of the central compartment was 4.5 +/- 6.7 liters/m2, volume of the peripheral compartment 10.6 +/- 1.4 liters/m2, distributional half-life 25 +/- 5.4 h, and elimination half-life 29.7 +/- 6.9 h. The terminal half-life was shorter than previously reported. These parameters were used as the initial population model for an iterative 2-stage analysis. The resulting distributional half-life of 22.3 +/- 2.7 h and elimination half-life of 28.2 +/- 5.0 h were similar, reflecting the intensive sampling. The iterative 2-stage analysis model was then used to determine the optimal sampling times and to simulate 20 data sets for a protocol designed to maintain plasma concentrations in a defined concentration range. This strategy is currently under investigation in phase I clinical trials.