Systems pharmacology and pharmacodynamics: An introduction

Systems pharmacology represents a hybrid, multi-scale modeling approach that seeks to combine systems or network-based structures with basic principles of pharmacokinetics and pharmacodynamics (PK/PD). Systems biology encompasses a broad spectrum of computational methods for vertically capturing molecular, cellular, and tissue level interactions that regulate biological systems. In contrast, PK/PD models are often minimal compartmental constructs (conceptual models) with parameters that integrate PK, drug-target interactions, and rate-limiting turnover processes. Both disciplines have shown value in various stages of drug development and utilization; however, there is growing interest in applying integrated systems pharmacology models, in a complimentary manner, for informing critical decisions in drug development and pharmacotherapy. Here we provide a rationale for the construction and evaluation of complex models of drug action that may serve to guide the development of new compounds and combinatorial regimens, explain sources of inter-subject variability in drug exposure and response, identify sources and influences of disease progression, and predict and understand drug efficacy and safety.