POPULATION PHARMACOKINETICS MODELING ON A SUPERCOMPUTER

潜在毒性药物的精确治疗需要最佳的方法来模拟患者的药代动力学/动力学(PK/PD)行为。在过去的两年中，我们在圣地亚哥超级计算机中心的大型并行Cray T3E机器上实现了有用的人口建模软件，创建了NCRR-USC-SDSC人口建模研究资源。这为这个计算密集的领域带来了可用的最好和最快的硬件和软件资源。一项在PC上工作一周的工作只需要几分钟的时间就可以使用这种资源。在这个竞争性的更新应用中，我们现在的目标是1)实现一种新的非参数建模算法，用于分析更大的模型；2)实现确定这种非参数模型的置信限的方法，目前还没有这种方法。对于非参数模型，这将首次允许在患者群体之间指示统计上显著的差异；3)开发检测过程噪声(微分方程式本身中的噪声)的方法，而不是目前不正确的处理环境噪声的方法，就好像它是测量中的噪声，特别是在非线性模型中，并检测随时间变化的参数值(一些全新的东西)；4)实施更优化的方法，以在最佳时间对受试者或患者的反应进行采样，避免目前的“第二条军规”，即人们应该提前知道参数值，以计算获得观察该系统的样本的最佳时间；以及5)升级资源的用户界面，使其更加用户友好和易于使用，并实施“最大熵”联合密度，以将旧的总体模型(其原始原始数据已经消失)转换为使用新的“多模型”剂量设计方法进行最佳治疗所需的离散联合密度。这一资源现在已被用于克服在较小机器上建立人口PK/PD模型的瓶颈，并用于量化艾滋病联合抗病毒治疗的共同效果。它可以在抗癌、抗菌和其他药物治疗中起到同样的作用。它将变得更加友好和有用，因为它为PC用户提供了一个新的类似Windows的用户界面，可以通过互联网和万维网轻松快速地访问。

Precise therapy with potentially toxic drugs demands optimal methods to model population with pharmacokinetic/dynamic (PK/PD) behavior in patients. In the past 2 years of our current 3 year project, we have implemented useful population modeling software on the San Diego Supercomputer Center's large parallel Cray T3E machine, creating an NCRR-USC-SDSC Research Resource for Population Modeling. which brings to this computationally intensive area the best and fastest hardware and software resources available. A job taking a week on a PC takes only a few minutes on this resource. In this competing renewal application, our aims now are 1) to implement a new non-parametric modeling algorithm for analysis of still larger models; 2) to implement methods for determining confidence limits for this non-parametric models, where none exist at present. This will, for the first time with non-parametric models, permit direction of statistically significant differences between populations of patients; 3) to develop methods to detect process noise (noise in the differential equations themselves) rather than the current incorrect method of dealing with environmental noise as if it were noise in the measurements, especially in non-linear models, and to detect changing parameter values over time (something totally new); 4) to implement still more optimal methods to sample subject or patient responses at optimal times, avoiding the current "Catch 2" that one is supposed to know the parameter values in advance in order to compute the optimal times to obtain samples for observing that system; and 5) to upgrade the user interface for the resource, making it more user- friendly and easy to use, and also to implement "maximum entropy" joint densities to convert old population models (whose original raw data is gone) to the discrete joint densities needed for optimal therapy with the new "multiple model" methods of dosage design. This resource has now been used to overcome the bottleneck in population PK/PD modeling on smaller machines, and to quantify the shared effects of combinatorial antiviral therapy for AIDS. It can do the same for anti-cancer, anti-bacterial, and other drug therapy. It will be even more friendly and useful with a new windows-like user interface for the PC user, easily and rapidly accessible over the internet and the world wide web.