用于描述不同大小的内源性和外源性蛋白质全身处置的转化双孔 PBPK 模型

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Shufang Liu, Yingyi Li, Zhe Li, Shengjia Wu, John M. Harrold, Dhaval K. Shah
{"title":"用于描述不同大小的内源性和外源性蛋白质全身处置的转化双孔 PBPK 模型","authors":"Shufang Liu, Yingyi Li, Zhe Li, Shengjia Wu, John M. Harrold, Dhaval K. Shah","doi":"10.1007/s10928-024-09922-x","DOIUrl":null,"url":null,"abstract":"<p>Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans. Datasets used for model development include more than 15 types of proteins: IgG (150 kDa), F(ab)2 (100 kDa), minibody (80 kDa), Fc-containing proteins (205, 200, 110, 105, 92, 84, 81, 65, or 60 kDa), albumin conjugate (85.7 kDa), albumin (67 kDa), Fab (50 kDa), diabody (50 kDa), scFv (27 kDa), dAb2 (23.5 kDa), proteins with an albumin-binding domain (26, 23.5, 22, 16, 14, or 13 kDa), nanobody (13 kDa), and other proteins (110, 65, or 60 kDa). The PBPK model incorporates: (i) molecular weight (MW)-dependent extravasation through large and small pores via diffusion and filtration, (ii) MW-dependent renal filtration, (iii) endosomal FcRn-mediated protection from catabolism for IgG and albumin-related modalities, and (iv) competition for FcRn binding from endogenous IgG and albumin. The finalized model can well characterize PK of most of these proteins, with area under the curve predicted within two-fold error. The model also provides insights into contribution of renal filtration and lysosomal degradation towards total elimination of proteins, and contribution of paracellular convection/diffusion and transcytosis towards extravasation. The PBPK model presented here represents a cross-modality, cross-species platform that can be used for development of novel biologics.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"45 1","pages":""},"PeriodicalIF":2.2000,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Translational two-pore PBPK model to characterize whole-body disposition of different-size endogenous and exogenous proteins\",\"authors\":\"Shufang Liu, Yingyi Li, Zhe Li, Shengjia Wu, John M. Harrold, Dhaval K. Shah\",\"doi\":\"10.1007/s10928-024-09922-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans. Datasets used for model development include more than 15 types of proteins: IgG (150 kDa), F(ab)2 (100 kDa), minibody (80 kDa), Fc-containing proteins (205, 200, 110, 105, 92, 84, 81, 65, or 60 kDa), albumin conjugate (85.7 kDa), albumin (67 kDa), Fab (50 kDa), diabody (50 kDa), scFv (27 kDa), dAb2 (23.5 kDa), proteins with an albumin-binding domain (26, 23.5, 22, 16, 14, or 13 kDa), nanobody (13 kDa), and other proteins (110, 65, or 60 kDa). The PBPK model incorporates: (i) molecular weight (MW)-dependent extravasation through large and small pores via diffusion and filtration, (ii) MW-dependent renal filtration, (iii) endosomal FcRn-mediated protection from catabolism for IgG and albumin-related modalities, and (iv) competition for FcRn binding from endogenous IgG and albumin. The finalized model can well characterize PK of most of these proteins, with area under the curve predicted within two-fold error. The model also provides insights into contribution of renal filtration and lysosomal degradation towards total elimination of proteins, and contribution of paracellular convection/diffusion and transcytosis towards extravasation. The PBPK model presented here represents a cross-modality, cross-species platform that can be used for development of novel biologics.</p>\",\"PeriodicalId\":16851,\"journal\":{\"name\":\"Journal of Pharmacokinetics and Pharmacodynamics\",\"volume\":\"45 1\",\"pages\":\"\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2024-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Pharmacokinetics and Pharmacodynamics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10928-024-09922-x\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Pharmacokinetics and Pharmacodynamics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10928-024-09922-x","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

基于生理学的双孔药代动力学(PBPK)模型已证明其在描述不同大小蛋白质的药代动力学(PK)方面具有潜力。然而,所有现有的双孔模型都缺乏用于验证或种间外推的多样化蛋白质。为了填补这一空白,我们开发并优化了一种转化型双孔 PBPK 模型,该模型可以描述不同大小蛋白质在小鼠、大鼠、猴子和人体内的血浆和组织处置。用于模型开发的数据集包括 15 种以上的蛋白质:IgG(150 kDa)、F(ab)2(100 kDa)、迷你体(80 kDa)、含 Fc 蛋白(205、200、110、105、92、84、81、65 或 60 kDa)、白蛋白共轭物(85.7 kDa)、白蛋白(67 kDa)、Fab(50 kDa)、二抗体(50 kDa)、scFv(27 kDa)、dAb2(23.5 kDa)、具有白蛋白结合结构域的蛋白质(26、23.5、22、16、14 或 13 kDa)、纳米抗体(13 kDa)以及其他蛋白质(110、65 或 60 kDa)。PBPK 模型包括:(i) 依赖分子量 (MW) 的外渗,通过大孔和小孔扩散和过滤;(ii) 依赖分子量的肾过滤;(iii) 内体 FcRn 介导的保护,使 IgG 和白蛋白相关模式免受分解;(iv) 内源性 IgG 和白蛋白对 FcRn 结合的竞争。最终确定的模型可以很好地描述大多数这些蛋白质的 PK 特性,预测的曲线下面积误差在两倍以内。该模型还提供了肾脏滤过和溶酶体降解对蛋白质总清除的贡献,以及细胞旁对流/扩散和转囊对外渗的贡献。本文介绍的 PBPK 模型是一个跨模式、跨物种的平台,可用于新型生物制剂的开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Translational two-pore PBPK model to characterize whole-body disposition of different-size endogenous and exogenous proteins

Translational two-pore PBPK model to characterize whole-body disposition of different-size endogenous and exogenous proteins

Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans. Datasets used for model development include more than 15 types of proteins: IgG (150 kDa), F(ab)2 (100 kDa), minibody (80 kDa), Fc-containing proteins (205, 200, 110, 105, 92, 84, 81, 65, or 60 kDa), albumin conjugate (85.7 kDa), albumin (67 kDa), Fab (50 kDa), diabody (50 kDa), scFv (27 kDa), dAb2 (23.5 kDa), proteins with an albumin-binding domain (26, 23.5, 22, 16, 14, or 13 kDa), nanobody (13 kDa), and other proteins (110, 65, or 60 kDa). The PBPK model incorporates: (i) molecular weight (MW)-dependent extravasation through large and small pores via diffusion and filtration, (ii) MW-dependent renal filtration, (iii) endosomal FcRn-mediated protection from catabolism for IgG and albumin-related modalities, and (iv) competition for FcRn binding from endogenous IgG and albumin. The finalized model can well characterize PK of most of these proteins, with area under the curve predicted within two-fold error. The model also provides insights into contribution of renal filtration and lysosomal degradation towards total elimination of proteins, and contribution of paracellular convection/diffusion and transcytosis towards extravasation. The PBPK model presented here represents a cross-modality, cross-species platform that can be used for development of novel biologics.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信