English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

Development of low‐clearance (CL) compounds that are slowly metabolized is a major goal in the pharmaceutical industry. However, the pursuit of low intrinsic CL (CL int ) often leads to significant challenges in evaluating the pharmacokinetics of such compounds. Although in vitro–in vivo extrapolation is widely used to predict human CL, its application has been limited for low‐CL int  compounds because of the low turnover of parent compounds in metabolic stability assays. To address this issue, we focused on chimeric mice with humanized livers (PXB‐mice), which have been increasingly reported to accurately predict human CL in recent years. The predictive accuracy for nine low‐CL int  compounds with no significant turnover in a human hepatocyte assay was investigated using PXB‐mouse methods, such as single‐species allometric scaling (PXB‐SSS) approach and a novel physiologically based scaling (PXB‐PBS) approach that assumes that the CL int  per hepatocyte is equal between humans and PXB‐mice. The percentages of compounds with predicted CL within 2‐ and 3‐fold ranges of the observed CL for low‐CL int  compounds were 89% and 100%, respectively, for both PXB‐SSS and PXB‐PBS approaches. Moreover, the predicted CL was mostly consistent among the methods. Conversely, the percentages of compounds with predicted CL within 2‐ and 3‐fold ranges of the observed CL for low‐CL int  compounds were 50% and 63%, respectively, for multispecies allometric (MA) scaling. Overall, these PXB‐mouse methods were much more accurate than conventional MA scaling approaches, suggesting that PXB‐mice are useful tools for predicting the human CL of low‐CL int  compounds that are slowly metabolized.

Prediction of human pharmacokinetics for low‐clearance compounds using pharmacokinetic data from chimeric mice with humanized livers