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.