First-in-Human Predictions of Hepatic Clearance for Drugs With the Well-Stirred Model: Comparative Assessment Between Models of Fraction Unbound Based Either on the Free Drug Hypothesis, Albumin-Facilitated Hepatic Uptake or Dynamic Binding Kinetics.

التفاصيل البيبلوغرافية
العنوان:	First-in-Human Predictions of Hepatic Clearance for Drugs With the Well-Stirred Model: Comparative Assessment Between Models of Fraction Unbound Based Either on the Free Drug Hypothesis, Albumin-Facilitated Hepatic Uptake or Dynamic Binding Kinetics.
المؤلفون:	Poulin P; Consultant Patrick Poulin Inc., Québec City, Québec, Canada; School of Public Health, Université de Montréal, Montréal, Québec, Canada. Electronic address: patrick-poulin@videotron.ca.
المصدر:	Journal of pharmaceutical sciences [J Pharm Sci] 2024 Aug; Vol. 113 (8), pp. 2641-2650. Date of Electronic Publication: 2024 May 24.
نوع المنشور:	Journal Article; Comparative Study
اللغة:	English
بيانات الدورية:	Publisher: Elsevier Country of Publication: United States NLM ID: 2985195R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-6017 (Electronic) Linking ISSN: 00223549 NLM ISO Abbreviation: J Pharm Sci Subsets: MEDLINE
أسماء مطبوعة:	Publication: 2016- : New York, NY : Elsevier Original Publication: Easton, Pa., American Pharmaceutical Assn.
مواضيع طبية MeSH:	Models, Biological* , Liver/metabolism , Protein Binding , Metabolic Clearance Rate*, Humans ; Pharmaceutical Preparations/metabolism ; Hepatocytes/metabolism ; Kinetics ; Albumins/metabolism ; Microsomes, Liver/metabolism ; Pharmacokinetics
مستخلص:	The well-stirred model (WSM) is commonly used to predict the hepatic clearance in vivo (CL H ) of drugs. The necessary intrinsic clearance of the unbound drug (CL int-in vitro-unbound ) is generated in the in vitro assays in the presence of microsomes or hepatocytes but in the absence of plasma proteins. The value of CL int-in vitro-unbound can be extrapolated with the fraction unbound determined in vitro in plasma (fu p ) only if the fraction unbound in vivo in liver is the same. However, this approach resulted to a systematic underprediction bias of CL H . With the goal of reducing this bias, two new models of fraction unbound were published in this journal. These models estimate the binding kinetics of the rates of association and dissociation of the drug-protein complex and propose that more dissociation in the liver compared to plasma will increase the fraction unbound available for the metabolism. Consequently, these two models generated higher values of fraction unbound, implying a lower underprediction bias of CL H with the WSM. The first model was developed by Poulin et al. and is referring to the value of fu p that is adjusted (fu -adjusted ) to quantify the effect of a full dissociation of the drug-protein complex at the hepatocyte membrane in accordance with the theory of the albumin-facilitated hepatic uptake. A second model was developed by Yan et al. who presented a dynamic fraction unbound (fu -dynamic ) measuring the real dissociation kinetics of the drug-protein complex with a new in vitro assay in the presence and absence of a recombinant liver enzyme in plasma. Therefore, the objective of this study was to make the first comparative assessment between these two models. The results indicate that, in general, the WSM combined with the values of fu -adjusted was the most accurate approach for predicting CL H . The WSM combined with the values of fu -dynamic has underperformed particularly with the acidic and neutral drugs binding to the albumin and presenting a low metabolic turnover in vitro. Therefore, the new in vitro assay for fu -dynamic gave an underprediction bias of CL H for these drug properties. However, the values of fu -adjusted are significantly higher than those values of fu -dynamic , and, this resulted to no underprediction bias, which is reinforcing the theory of the ALB-facilitated hepatic uptake. For the other neutral and acidic drugs, the models of fu -dynamic and fu -adjusted are in closer agreement. Finally, for the basic drugs, the models of fu -adjusted and fu -dynamic as well as a third model only considering a pH gradient effect on fu p are almost accurately equivalent. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)
فهرسة مساهمة:	Keywords: Albumin-mediated; Clearance; DMPK; Dynamic well-stirred model; First-in-humans; IVIVE; In vitro-to-in vivo extrapolations; PBPK modeling; Pharmacokinetics; Uptake
المشرفين على المادة:	0 (Pharmaceutical Preparations) 0 (Albumins)
تواريخ الأحداث:	Date Created: 20240525 Date Completed: 20240828 Latest Revision: 20240911
رمز التحديث:	20240911
DOI:	10.1016/j.xphs.2024.05.021
PMID:	38796154
قاعدة البيانات:	MEDLINE

الوصف
تدمد:	1520-6017
DOI:	10.1016/j.xphs.2024.05.021