Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

Author:

Kemas Aurino M.1,Zandi Shafagh Reza1234,Taebnia Nayere1,Michel Maurice5,Preiss Lena16,Hofmann Ute2,Lauschke Volker M.123ORCID

Affiliation:

1. Department of Physiology and Pharmacology Karolinska Institutet Stockholm 17177 Sweden

2. Dr. Margarete Fischer‐Bosch Institute of Clinical Pharmacology 70376 Stuttgart Germany

3. University of Tuebingen 72074 Tuebingen Germany

4. Division of Micro‐ and Nanosystems KTH Royal Institute of Technology Stockholm 10044 Sweden

5. Department of Oncology and Pathology Science for Life Laboratory Karolinska Institutet Stockholm 17165 Sweden

6. Department of Drug Metabolism and Pharmacokinetics (DMPK) Merck KGaA 64293 Darmstadt Germany

Abstract

AbstractOrganotypic and microphysiological systems (MPS) that can emulate the molecular phenotype and function of human tissues, such as liver, are increasingly used in preclinical drug development. However, despite their improved predictivity, drug development success rates have remained low with most compounds failing in clinical phases despite promising preclinical data. Here, it is tested whether absorption of small molecules to polymers commonly used for MPS fabrication can impact preclinical pharmacological and toxicological assessments and contribute to the high clinical failure rates. To this end, identical devices are fabricated from eight different MPS polymers and absorption of prototypic compounds with different physicochemical properties are analyzed. It is found that overall absorption is primarily driven by compound hydrophobicity and the number of rotatable bonds. However, absorption can differ by >1000‐fold between polymers with polydimethyl siloxane (PDMS) being most absorptive, whereas polytetrafluoroethylene (PTFE) and thiol‐ene epoxy (TEE) absorbed the least. Strikingly, organotypic primary human liver cultures successfully flagged hydrophobic hepatotoxins in lowly absorbing TEE devices at therapeutically relevant concentrations, whereas isogenic cultures in PDMS devices are resistant, resulting in false negative safety signals. Combined, these results can guide the selection of MPS materials and facilitate the development of preclinical assays with improved translatability.

Funder

Horizon 2020 Framework Programme

Knut och Alice Wallenbergs Stiftelse

Vetenskapsrådet

Publisher

Wiley

Subject

Pharmaceutical Science,Biomedical Engineering,Biomaterials

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