Jodrell D I, Reyno L M, Sridhara R, Eisenberger M A, Tkaczuk K H, Zuhowski E G, Sinibaldi V J, Novak M J, Egorin M J
Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore 21202.
J Clin Oncol. 1994 Jan;12(1):166-75. doi: 10.1200/JCO.1994.12.1.166.
This study aimed to (1) develop a population pharmacokinetic model for suramin; (2) use Bayesian methods to assess suramin pharmacokinetics in individual patients; (3) use individual patients' pharmacokinetic parameter estimates to individualize suramin dose and schedule and maintain plasma suramin concentrations within predetermined target ranges; and (4) assess the feasibility of outpatient administration of suramin by intermittent, short infusions.
Plasma suramin concentrations were measured by high-performance liquid chromatography (HPLC), and compartmental pharmacokinetic models were fit using a Bayesian algorithm. Population pharmacokinetic models were developed using an iterative two-stage approach. Estimates of each patient's central-compartment volume were used to calculate suramin dosage. Simulation of that patient's suramin clearance was used to predict the time of his next dose. Using this approach, plasma suramin concentration was maintained at between 200 and 300, 175 and 275, 150 and 250, or 100 and 200 microgram/mL in four sequential patient cohorts. The ability of two- and three-compartment, open, linear models to fit the pharmacokinetic data was compared. Population pharmacokinetic parameters were estimated, using both two- and three-compartment structural models in 69 hormone-refractory prostate cancer patients.
Target plasma suramin concentrations in individual patients were rapidly achieved. Concentrations were maintained within desired ranges for > or = 85% of treatment duration in all cohorts. A three-compartment, open, linear model described suramin pharmacokinetics better than did a two-compartment, open, linear model. Population pharmacokinetic estimates generated for two- and three-compartment pharmacokinetic models demonstrated modest interpatient pharmacokinetic variability and the long terminal half-life of suramin.
Suramin can be administered by intermittent short infusion. Adaptive-control-with-feedback dosing facilitated precise control of plasma suramin concentrations and allowed a number of different concentration ranges to be studied. This approach is expensive and labor-intensive. Although we have demonstrated the ability to control drug exposure, simpler dosing schedules require critical evaluation. Population pharmacokinetic parameters generated in men with hormone-refractory prostate cancer will facilitate rational design of such schedules.
本研究旨在（1）建立苏拉明的群体药代动力学模型；（2）使用贝叶斯方法评估个体患者的苏拉明药代动力学；（3）使用个体患者的药代动力学参数估计值来个体化苏拉明的剂量和给药方案，并将血浆苏拉明浓度维持在预定的目标范围内；（4）评估通过间歇性短时间输注在门诊给予苏拉明的可行性。
采用高效液相色谱法（HPLC）测定血浆苏拉明浓度，并使用贝叶斯算法拟合房室药代动力学模型。群体药代动力学模型采用迭代两阶段法建立。利用每位患者中央室容积的估计值来计算苏拉明剂量。模拟该患者的苏拉明清除率以预测其下次给药时间。采用这种方法，在四个连续的患者队列中，将血浆苏拉明浓度维持在200至300、175至275、150至250或100至200微克/毫升之间。比较了二室和三室开放线性模型拟合药代动力学数据的能力。在69例激素难治性前列腺癌患者中，使用二室和三室结构模型估计群体药代动力学参数。
个体患者的目标血浆苏拉明浓度迅速达到。在所有队列中，浓度在治疗持续时间的≥85%内维持在期望范围内。三室开放线性模型比二室开放线性模型能更好地描述苏拉明的药代动力学。二室和三室药代动力学模型生成的群体药代动力学估计值显示患者间药代动力学变异性适中，且苏拉明的终末半衰期较长。
苏拉明可通过间歇性短时间输注给药。反馈给药的自适应控制有助于精确控制血浆苏拉明浓度，并允许研究多种不同的浓度范围。这种方法昂贵且劳动强度大。尽管我们已证明有能力控制药物暴露，但更简单的给药方案仍需严格评估。激素难治性前列腺癌男性患者生成的群体药代动力学参数将有助于合理设计此类给药方案。
