PK-Informed Microphysiological Systems: From Dynamic Dosing to Quantitative In Vitro–In Vivo Translation

Conventional in vitro drug evaluation relies largely on static concentration–response assays that fail to reproduce the dynamic pharmacokinetic (PK) profiles observed in vivo, contributing to the gap between preclinical findings and clinical outcomes. Recent advances in microphysiological systems (MPSs), particularly microfluidic organ-on-chip platforms, enable programmable concentration–time profiles that more closely mimic physiological drug exposure. These PK-informed platforms allow systematic investigation of schedule dependency, time-dependent pharmacodynamics (PD), and exposure-driven efficacy under controlled flow conditions. Spatially resolved analytical approaches further reveal heterogeneous drug penetration and metabolic responses within tissues, emphasizing the importance of spatiotemporal PK–PD coupling. Integration of multi-organ and vascularized chip systems with physiologically based pharmacokinetic (PBPK) modeling increasingly supports quantitative in vitro–in vivo translation. This review outlines how PK-informed MPSs can generate dynamic in vitro exposure and response data that inform PBPK modeling, thereby supporting quantitative in vitro–in vivo translation of drug disposition and response.