POPULATION PHARMACOKINETICS MODELING ON A SUPERCOMPUTER

潜在毒性药物的精确治疗需要最佳方法来模拟具有患者药代动力学/动力学（PK/PD）行为的群体。在我们目前的3年项目的过去2年中，我们已经在圣地亚哥超级计算机中心的大型并行Cray T3 E机器上实现了有用的人口建模软件，为人口建模创建了NCRR-USC-SDSC研究资源。这为该计算密集型区域带来了可用的最佳和最快的硬件和软件资源。在PC上花费一周时间的作业在此资源上只需几分钟。在这个竞争性的更新应用程序中，我们现在的目标是：1）实现一个新的非参数建模算法，用于分析更大的模型; 2）实现确定非参数模型置信限的方法，目前还不存在。这将是第一次使用非参数模型，允许指导患者群体之间的统计学显著差异; 3）开发检测过程噪声的方法（微分方程本身中的噪声），而不是当前处理环境噪声的不正确方法，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（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反应进行采样，避免当前的“第二条军规”假设人们预先知道参数值，以便计算获得用于观察该系统的样本的最佳时间;以及5）更新资源的用户界面，使其更加用户友好和易于使用，并实现“最大熵”联合密度转换旧的人口模型（其原始原始数据已经消失）到使用剂量设计的新的“多模型”方法进行最佳治疗所需的离散关节密度。该资源现已被用于克服在较小机器上进行群体PK/PD建模的瓶颈，并量化艾滋病组合抗病毒治疗的共同效果。它也可以用于抗癌、抗菌和其他药物治疗。它将更加友好和有用，为个人电脑用户提供一个新的类似窗口的用户界面，可以通过互联网和万维网方便快捷地访问。

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.