Abstract
Accurate prediction of in vivo hepatic clearance is an essential part of successful and efficient drug development; however, many investigators have recognized that there are significant limitations in the predictability of clearance with a tendency for underprediction for primarily metabolized drugs. Here, we examine the impact of adding serum or albumin into hepatocyte and microsomal incubations on the predictability of in vivo hepatic clearance. The addition of protein into hepatocyte incubations has been reported to improve the predictability for high clearance (extraction ratio) drugs and highly protein-bound drugs. Analyzing published data for 60 different drugs and 97 experimental comparisons (with 17 drugs being investigated from two to seven) we confirmed the marked underprediction of clearance. However, we could not validate any relevant improved predictability within twofold by the addition of serum to hepatocyte incubations or albumin to microsomal incubations. This was the case when investigating all measurements, or when subdividing analyses by extraction ratio, degree of protein binding, Biopharmaceutics Drug Disposition Classification System class, examining Extended Clearance Classification System class 1B drugs only, or drug charge. Manipulating characteristics of small data sets of like compounds and adding scaling factors can appear to yield good predictability, but the carryover of these methods to alternate drug classes and different laboratories is not evident. Improvement in predictability of poorly soluble compounds is greater than that for soluble compounds, but not to a meaningful extent. Overall, we cannot confirm that protein addition improves in vitro-in vivo extrapolation predictability to any clinically meaningful degree when considering all drugs and different subsets.
SIGNIFICANCE STATEMENT The addition of protein into microsomal or hepatocyte incubations has been widely proposed to improve hepatic clearance predictions. To date, studies examining this phenomenon have not included appropriate negative controls where predictability is achieved without protein addition and have been conducted with small data sets of similar compounds that don’t apply to alternate drug classes. Here, an extensive analysis of published data for 60 drugs and 97 experimental comparisons couldn’t validate any relevant clinically improved clearance predictability with protein addition.
Footnotes
- Received September 13, 2021.
- Accepted January 21, 2022.
↵1 Current affiliation: Pharmacokinetics and Safety Assessment Department, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
↵2 Current affiliation: Department of Drug Metabolism and Pharmacokinetics, Plexxikon Inc., South San Francisco, California.
This work was supported by a Mary Anne Koda-Kimble Seed award for innovation; a grant from Nippon Shinyaku Co., Ltd., Japan (to T. K.); an American Foundation for Pharmaceutical Education Pre-Doctoral Fellowship (to J.K.S.); National Institutes of Health National Institute of General Medical Sciences [Grant R25-GM568470] (to J.K.S.); a Louis Zeh Fellowship (to J.K.S.); and National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant P30-DK026743] (to L.Z.B.).
No author has an actual or perceived conflict of interest with the contents of this article.
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- Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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