Physiologically Based Pharmacokinetic and Pharmacodynamic Analysis Enabled by Microfluidically Linked Organs-on-Chips

Abstract

Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches are beginning to be integrated into drug development and approval processes because they enable key pharmacokinetic (PK) parameters to be predicted from in vitro data. However, these approaches are hampered by many limitations, including an inability to incorporate organ-specific differentials in drug clearance, distribution, and absorption that result from differences in cell uptake, transport, and metabolism. Moreover, such approaches are generally unable to provide insight into pharmacodynamic (PD) parameters. Recent development of microfluidic Organ-on-a-Chip (Organ Chip) cell culture devices that recapitulate tissue-tissue interfaces, vascular perfusion, and organ-level functionality offer the ability to overcome these limitations when multiple Organ Chips are linked via their endothelium-lined vascular channels. Here, we discuss successes and challenges in the use of existing culture models and vascularized Organ Chips for PBPK and PD modeling of human drug responses, as well as in vitro to in vivo extrapolation (IVIVE) of these results, and how these approaches might advance drug development and regulatory review processes in the future.

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

“…In this context, a plethora of multiorgan systems have been presented, in which a organotypic hepatic model is integrated with models of other tissues in perfused devices. However, as these applications are outside of the scope of this review, we refer the interested reader to excellent recent reviews on this matter …”

“…However, as these applications are outside of the scope of this review, we refer the interested reader to excellent recent reviews on this matter. [32][33][34]…”

A robotic platform for fluidically-linked human body-on-chips experimentation

“…Microfluidic Organ Chip devices with perfused endothelial and parenchymal channels and multi-organ microphysiological systems have the potential to overcome these limitations 6,7,9,53 . For example, unlike most past PK models, here we leveraged the biomimetic design of Organ Chips to conduct full 3D simulations of mass transport without the pitfalls of well-stirred reactor assumptions.…”

“…multi-organ, HuBoC systems that recapitulate organ-level functions to facilitate studies of drug pharmacokinetics and pharmacodynamics (PK/PD) in vitro [6][7][8][9][10][11] . An automated experimental system that can meet these goals needs to be highly multifunctional and must ideally enable fluid handling and sample collection, perfusion of fluid through multiple linked microfluidic Organ Chip devices, and tissue imaging, all within a controlled temperature, humidity, and CO2 environment.…”

Introduction to the Theme “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development”

“…Such microphysiological systems can create Organs-on-Chips and provide novel ways to assess pharmacokinetics, pharmacodynamics, and drug-drug and drug-toxicant interactions. Progress in the creation, validation, and utilization of such systems is reviewed in the articles by Prantil-Baun et al (6) and Ewart et al (7).…”