MatTek Giving Keynote Talk at AAPS 2019

Posted on October 30, 2019 |
Categories Posters, News, Meetings

3D Intestinal Tissues for Lead Optimization, Safety, and Permeability

Tuesday, November 5, 10-10:30 am

Description: Availability of human primary cell-based 3D small intestinal microtissues that recapitulate structural and functional mimicry with the in vivo counterpart is critical to obtain reproducible in vitro testing tools to predict safety and bioavailability of compounds for oral administration and other xenobiotics. These 3D intestinal tissue models bridge the gap in preclinical testing to predict safety. Data from a panel of 30 benchmark drugs with known human absorption values that were evaluated on the intestinal tissue model will be presented. Study results of drug-drug interactions and drug metabolism will be shared. The functionality and limitations of these models for GI toxicity studies will be discussed.

Attending the meeting? Visit Seyoum at his poster presentation:

Drug Toxicity and Permeability Screening Using a Reproducible In Vitro 3D-Human Small Intestinal Tissue Model
Seyoum Ayehunie, Jan Markus, Timothy Landry, Zachary Stevens, and Alex Armento

Monday, November 4, 9:30 AM – 10:30 AM

Purpose: The purpose of the study is to investigate the reliability and reproducibility of in vitro models and their use in predicting drug absorption. Characterization of the microtissues included evaluation of structural features, barrier properties, and expression of drug transporters and drug-metabolizing enzymes.
Methods: The quality and reproducibility of tissue production were compared in two independent production facilities (MatTek, Ashland, MA, USA and IVLSL, Bratislava, Slovakia) by measuring TEER and Lucifer Yellow (LY) leakage. To evaluate the suitability of the microtissues for drug absorption, the apparent permeability coefficient (Papp) values for a panel of benchmark drugs with known human absorption values were measured. Drug-drug interactions were examined using drugs known to be substrates or inhibitors of efflux transporters. Structural features were monitored by histology
Results: Results showed that tissues are highly reproducible with physiological TEER values averaging 146.4±20.8 Ω*cm2 (% CV=14.2%) in the USA (N=128 lots) and 162.6±10.2 Ω*cm2 in Slovakia (N=60 lots) facilities. The real-time PCR analysis revealed that microtissues expressed all tested drug transporters and metabolizing enzymes known to be present in vivo. Drug permeation analysis with 18 selected drugs showed that the intestinal microtissues could discriminate between low and high permeability drugs with 94% accuracy. The in vitro Papp values correlated well with human absorption data. SMI microtissues show an active efflux transport as when exposed to substrates of ABC pumps, the resulting drug efflux ratios were > 2.0. Moreover, the addition of efflux transporter inhibitors reduced the drug efflux ratio while increasing the bioavailability of the test drugs, providing further evidence of ABC transporter activity.
Conclusion: The SMI microtissues appear to be a promising tool for predicting the safety and bioavailability of orally administered drugs.

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