Application of Quantitative Biomeasures in Early Drug Discovery

Mathematical models of drug action are essential in contemporary drug discovery and development. Applications include exposure-response modeling (pharmacokinetics-pharmacodynamics or PK-PD); quantitative understanding of biological target and pathway; and systems approaches that integrate characteristics of the biological system with associated drug exposure. Encompassing empirical, mechanistic, or semi-mechanistic approaches, these mathematical models are informed by experimental data quantifying not only drug exposure (pharmacokinetics) and associated biological response (biomarkers), but also system-specific parameters intermediate between drug exposure and response. These system-specific endpoints, or biomeasures, include target-specific measurements such as density, turnover, shedding, and internalization rate. Quantifying these pharmacokinetic and pharmacodynamic endpoints—which include small molecule, biological, and cellular measures—requires a diverse repertoire of analytical instrumentation and approaches. The discipline partnership between quantitative bioanalytics and systems modeling provides an invaluable tool to improve the success of pharmaceutical research and development. The authors will provide a perspective on the interface between laboratory science and mathematical modeling to improve assessment of exposure-response relationships, and ultimately successful drug development.