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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Application of population pharmacokinetics to the phase II development of an anti-Alzheimer's disease compound, S12024.
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Application of population pharmacokinetics to the phase II development of an anti-Alzheimer's disease compound, S12024.

机译：群体药代动力学在抗阿尔茨海默氏病化合物S12024的II期开发中的应用。

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摘要

Steady-state concentrations of S12024, a novel compound for treatment of Alzheimer's disease, were studied to determine the pharmacokinetic parameters of S12024 in Phase IIa patients and to assess the effect of patient characteristics on those pharmacokinetics. A prospective sparse sampling strategy was used to obtain oral repeated data (n = 285) from 89 patients, which were analyzed using a one-compartment model and the NONMEM computer program. The model suggested that apparent clearance of S12024 was influenced by the study and by patient age. In the Spanish study, apparent clearance was increased by 68% and 26% for doses of 100 mg and 300 mg, respectively, and patient age decreased oral clearance by approximately 10% per decade in the patient age range (50 to 90 years). Data from only a few patients in the Spanish study were probably responsible for the observed study influence on apparent clearance of S12024, and no measured covariates could explain this effect. The model provided an excellent characterization of the observed data and it predicted correctly the plasma concentrations from an earlier Phase I trial and a subsequent Phase IIb study. The present model, built from Phase IIa data, provides a basis for examining the influence of patient covariates and the magnitude of their effects on the pharmacokinetics of S12024. The study effect is probably an artefact that will disappear by further expanding of the population model in the future.
机译：研究了用于治疗阿尔茨海默氏病的新型化合物S12024的稳态浓度，以确定S12024在IIa期患者中的药代动力学参数，并评估患者特征对这些药代动力学的影响。前瞻性稀疏采样策略用于从89例患者中获得口头重复数据（n = 285），这些数据使用一室模型和NONMEM计算机程序进行了分析。该模型表明，S12024的表观清除率受研究和患者年龄的影响。在西班牙的研究中，在100毫克和300毫克的剂量下，表观清除率分别增加了68％和26％，并且在患者年龄范围（50至90岁）中，患者年龄每十年降低了口服清除率约10％。西班牙研究中仅来自少数患者的数据可能是所观察到的研究对S12024表观清除率的影响，并且没有测量的协变量可以解释这种作用。该模型对观察到的数据进行了很好的表征，并且可以从较早的I期试验和随后的IIb期研究中正确预测血浆浓度。从IIa期数据构建的本模型为检查患者协变量的影响及其对S12024药代动力学的影响程度提供了基础。研究效果可能是伪像，将来会随着人口模型的进一步扩展而消失。

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