All-Human Tri-culture Hepatic Model to Evaluate Cytochrome P450 2C Induction Risk: Quantitative Assessment Using Physiologically Based Pharmacokinetic Modeling

All-Human Tri-culture Hepatic Model to Evaluate Cytochrome P450 2C Induction Risk: Quantitative Assessment Using Physiologically Based Pharmacokinetic Modeling | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 15 March 2025 V1 Latest version Share on All-Human Tri-culture Hepatic Model to Evaluate Cytochrome P450 2C Induction Risk: Quantitative Assessment Using Physiologically Based Pharmacokinetic Modeling Authors : Marina Slavsky [email protected] , Aniruddha Sunil Karve , Diane Ramsden , and Niresh Hariparsad Authors Info & Affiliations https://doi.org/10.22541/au.174203836.67044255/v1 249 views 148 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Cytochrome P450 (CYP)3A is involved in the metabolism of more than 50% of prescribed drugs, and reports indicate that 70% of CYP3A inducers are also CYP3A inhibitors, thereby complicating the interpretation of induction based DDI potential and reducing the confidence in clinical outcome extrapolation for co-regulated enzymes such as CYP2C8, 2C9 and 2C19. While the preclinical assessment of CYP3A4 induction has been conducted extensively, the evaluation of CYP2C induction is hindered by low dynamic response in standard monoculture hepatocyte models, which may prompt additional clinical DDI investigations. This study was aimed to characterize the induction potential of CYP2C enzymes in all human hepatocyte triculture model (HTC), a two-dimensional hepatic system with human primary hepatocytes, stromal, and endothelial cells. The in vitro induction potential of known inducers of CYP2C8, CYP2C9, CYP2C19 and CYP3A was assessed using the HTC model. In addition, hepatocytes from a single donor were plated in the sandwich culture (SC) model for direct comparison of induction endpoints and the induction parameters were used for simulating clinical PK implications. RNA-seq results showed distinct basal expression differences in CYPs, transporters and transcription factors between both models, potentially suggesting better recapitulation of native liver hepatocytes in the HTC model. Compared to SC, the HTC model showed robust induction of CYP2C. By incorporating the induction parameters obtained from the HTC model into PBPK models, an excellent correlation was obtained relative to clinical outcomes for CYP2C8, CYP2C9, CYP2C19 and CYP3A4. Overall, this study provides a potential approach to quantitatively assess CYP2C-induction risk preclinically. Supplementary Material File (figures.pptx) Download 2.07 MB File (ivive truvivo_manuscript_final.docx) Download 209.42 KB File (tables.pptx) Download 61.73 KB Information & Authors Information Version history V1 Version 1 15 March 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords clinical pharmacology drug metabolism hepatopharmacology metabolism pharmacokinetics systems pharmacology Authors Affiliations Marina Slavsky [email protected] AstraZeneca Pharmaceuticals LP View all articles by this author Aniruddha Sunil Karve AstraZeneca Pharmaceuticals LP View all articles by this author Diane Ramsden AstraZeneca Pharmaceuticals LP View all articles by this author Niresh Hariparsad AstraZeneca Pharmaceuticals LP View all articles by this author Metrics & Citations Metrics Article Usage 249 views 148 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Marina Slavsky, Aniruddha Sunil Karve, Diane Ramsden, et al. All-Human Tri-culture Hepatic Model to Evaluate Cytochrome P450 2C Induction Risk: Quantitative Assessment Using Physiologically Based Pharmacokinetic Modeling. Authorea . 15 March 2025. DOI: https://doi.org/10.22541/au.174203836.67044255/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. 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