Linear-In-Flux-Expressions Methodology: Toward a Robust Mathematical Framework for Quantitative Systems Pharmacology Simulators.

Quantitative Systems Pharmacology (QSP) modeling is increasingly used as a quantitative tool for advancing mechanistic hypotheses on the mechanism of action of a drug, and its pharmacological effect in relevant disease phenotypes, to enable linking the right drug to the right patient. Application of QSP models relies on creation of virtual populations for simulating scenarios of interest. Creation of virtual populations requires 2 important steps, namely, identification of a subset of model parameters that can be associated with a phenotype of disease and development of a sampling strategy from identified distributions of these parameters. We improve on existing sampling methodologies by providing a means of representing the structural relationship across model parameters and describing propagation of variability in the model. This gives a robust, systematic method for creating a virtual population. We have developed the Linear-In-Flux-Expressions (LIFE) method to simulate variability in patient pharmacokinetics and pharmacodynamics using relationships between parameters at baseline to create a virtual population. We demonstrate the importance of this methodology on a model of cholesterol metabolism. The LIFE methodology brings us a step closer toward improved QSP simulators through enhanced capture of the observed variability in drug and disease clinical data.