Utility of Common In Vitro Systems for Predicting Circulating Metabolites.

Area of Science:

• Pharmacology
• Drug Metabolism
• Toxicology

Background:

• In vitro systems are crucial for early drug development, predicting human metabolites and guiding preclinical species selection for toxicity studies.
• However, the predictive accuracy of in vitro models for in vivo outcomes can be variable, necessitating a clearer understanding of their reliability.
• Assessing the correlation between in vitro and in vivo metabolite profiles is vital for de-risking drug development decisions.

Purpose of the Study:

• To evaluate the ability of in vitro systems to predict circulating metabolites observed in vivo.
• To determine if the predictivity of in vitro systems is quantitative or merely indicative of metabolite presence.
• To compare the performance of common in vitro liver models in generating predictive metabolites for human drug metabolism.

Main Methods:

• A retrospective analysis of historical metabolite profiling data from Abbott/AbbVie was conducted, comparing in vitro and in vivo (absorption, distribution, metabolism, excretion, and clinical) study results.
• Ten commercially available compounds with published metabolism data were incubated in five in vitro systems: microsomes, liver S9, suspension hepatocytes, HμREL cocultured hepatocytes, and hepatocyte spheroids.
• New in vitro metabolite profiling data were generated and compared against published in vivo data to assess the accuracy of each system in predicting known major human circulating metabolites.

Main Results:

• In vitro systems predicted approximately 50% of circulating metabolites found in vivo across preclinical species and humans.
• No quantitative correlation was observed between metabolite concentrations measured in vitro and those found in vivo.
• Suspension hepatocytes and cocultured hepatocytes marginally outperformed other tested in vitro systems in predicting known major human circulating metabolites.

Conclusions:

• Current in vitro systems are valuable for early drug development when in vivo studies are not feasible and for regulatory filings supporting preclinical toxicology species selection.
• While in vitro systems predict the presence of about half of circulating metabolites, they do not provide quantitative level predictions.
• No single in vitro system definitively outperforms others, though suspension and cocultured hepatocytes showed slightly better predictive performance; these systems should not be considered wholly representative of in vivo drug metabolism.