Novel Milli-fluidic Human Liver Tissue Chip and Multi-tissue Chip Platform with Continuous Recirculation for Predictive Pharmacokinetic Applications

Abstract ID 92860 Poster Board 229 The optimization of drug properties to develop efficacious and safe therapies for humans is a critical step in preclinical discovery. Although efforts have been made to develop in vitro methods that deliver translational and predictive data, much testing still utilizes animal models, which create a large financial burden during lead optimization and can be inaccurate in predicting human outcomes. Furthermore, after the 2022 FDA Modernization Act 2.0, the need for in vitro-based new approach methodologies (NAM), is drastically increased. To address this need, we have developed an integrated platform that combines human tissue chips with translational software to predict clinical parameters of investigational drugs. Human tissue chips, aka microphysiological systems (MPS), are traditionally microfluidic devices designed to recapitulate human physiology at the tissue level and enable long-term in vitro (co-)cultures. While current microfluidic-based tissue chips are primarily used in basic research, such technologies have limited utility in developing NAMs for pharmacokinetic applications because the flow-through fluidic design, high non-specific binding of small molecule compounds, and small media & tissue volumes do not support drug quantification. Javelin's single- and multi-tissue chips are designed to generate multi-scale (media- and tissue-based) data by incorporating media recirculation in a COC-based milli-fluidic chip with larger media volumes (>1ml) and tissue sizes (>200K cells per tissue) than other microfluidic chips. We developed novel liver tissue chip (LTC) and multi-tissue chip (MTC) integrating liver-kidney-muscle MPS and evaluated its human-relevance with phenotypic characterization including morphology, in vitro and clinical biomarkers and gene expression similarities. In Rajan et al, we demonstrated LTC exhibits minimal non-specific binding of drugs of varying ionic states and lipophilicity. LTC allows long-term metabolically active primary hepatic MPS with sustained metabolic CYP activity for at least 15 days. This long-term culture was then used for drug clearance studies for low and high-clearance compounds for at least 12 days and clearance was estimated for a range of compounds with high in vitro in vivo correlation (IVIVC). Liver, kidney, and muscle MPS were also integrated on MTC and were evaluated both for pharmacokinetic context of use applications (manuscript in preparation). Then, a diverse set of compounds were tested on each tissue and tissue-specific pharmacokinetic parameters (such as hepatic and renal clearance and volume of distribution) were measured. Then, on-chip results were extrapolated to human scale with companion software using quantitative systems pharmacology (QSP)-based algorithms to quantify predictability of each CoU application. The predicted PK (CLint, CLr and VDss) parameters showed high correlation to clinical parameters. These studies demonstrated that the Javelin Biotech platform can deliver accurate clinical predictions for several applications, and offer an alternative to, and hopefully a replacement of, laboratory animal studies for the purposes of understanding human pharmacokinetics in an intact mammal as a surrogate for human. Rajan, S.A.P., Sherfey, J., Ohri, S. et al. A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications. AAPS J25, 102 (2023). https://doi.org/10.1208/s12248-023-00870-x