Microphysiological systems for ADME-related applications: current status and recommendations for system development and characterization

Abstract

Potential applications of MPS in the ADME discipline.

Characterizing the reproducibility in using a liver microphysiological system for assaying drug toxicity, metabolism, and accumulation

“…One challenge facing widespread MPS implementation is the difficulty in transferring MPSs to drug development laboratories from academic groups, which often have the advantage of unique expertise in microfabrication and instrumentation methods, or semi-exclusive access to cell types. In addition to efforts from industry, 2,3 testing centers have been created to address such translational hurdles, and initial results demonstrated the need of different drug development stakeholders for generating key characterization data on MPS use. 15,33,34 In the current study, experiments conducted in PHHs used the same batch of cells to ensure a primary focus on the reliability of MPS operation and to eliminate batch effects.…”

“…13,14 Proof of concept results from pilot studies performed upon the prototyping of MPSs upheld their potential utility in drug discovery and motivated drug development stakeholders to start investigating performance standards for risk assessment uses or for predicting drug absorption, distribution, metabolism and excretion (ADME). 2,3 This study addresses the need for performance standards of liver MPSs for general uses in drug pharmacology and toxicology, as applications in these fields rely on the metabolic function of cells, the stability and robustness of their function and on their response to hepatotoxic compounds. 1 Prior to establishing specific contexts of use for MPSs, where the technology may demonstrate clear advantages over current approaches and tools, the reproducibility of a systems' performance should be tested to ensure adequate reliability for drug evaluation, especially when considering applications in the later stages of drug development, where MPSs are acknowledged to hold great potential in replacing, reducing or refining animal tests or clinical trials.…”

“…In addition, a more stable function in the tested MPS and the observed CYP3A4 activity and expression of ADME genes (Figures 5D, 5E, S13 and S14) met additional requirements for liver MPSs. 2,3 Use of a media volume of 1.6 mL (Table S3), low nonspecific binding of compounds to the MPS (Figure S12), recirculation of media and use of sufficient cellular mass were other characteristics that met criteria for ADME applications. 3 The observed disparities in toxicant responses using the same batch of cells (Figure 2 and Table 1) may indicate…”

“…When assessing drug toxicity, metabolism, and transport, the liver is the central organ of study, and among the most common MPS modalities for drug development applications. [1][2][3] Liver MPSs are designed to maintain hepatocyte-like cells or…”

Organs-on-chips: into the next decade

“…Additionally, there is a growing need to predict the toxicity of novel modalities such as biologics, oligonucleotides and large molecules (MW > ~900 Da) that are challenging or impossible to assess in standard animal models. OoCs may have advantages for these modality-specific assessments by allowing modeling of complex human responses in tightly-controlled in vitro systems that may be linked to model organ crosstalk 56 and can be designed for specific contexts of use 57 .…”