Accelerating robust plausible virtual patient cohort generation by substituting ODE simulations with parameter space...

The generation of plausible virtual patients (VPs) is an important step in most quantitative systems pharmacology (QSP) workflows, which requires time-intensive solving of ordinary differential equations (ODEs). However, non-physiological profiles of outputs of interest (OoI) are frequently produced, and additional acceptance/rejection steps are needed for comparing and removing VPs with predicted values outside a pre-defined range. Here, a new approach is developed to accelerate the acceptance/rejection steps by leveraging patterns of parameter associations with OoI. In most models, some parameters are monotonic with respect to OoI, such that an increase in a parameter value always induces an increase or decrease in the OoI. This monotonic property can be used to replace some ODE-solving steps with appropriate monotonic parameter value comparisons to extrapolate the rejection or interpolate the acceptance of some VPs (after simulation) to others. Two algorithms were built that directly extract plausible VPs from a pre-defined initial cohort. These algorithms were first tested using a simple tumor growth inhibition model. Analyzing 200,000 VPs took 50 s with a reference method and 3 to 41 s (depending on the initial set-up) with the first algorithm. The method was then applied to an apoptosis QSP model, in which the clinical phenotypes (i.e., treatment sensitive or resistant) of 200,000 VPs were fully characterized for four different drug regimens in 12 min as compared to over 80 min with the reference approach. Extraction of each phenotype can also be performed individually in 34 s to 8 min, demonstrating the time benefit and flexibility of this approach.