Pulmonary Pharmacokinetics of Antibody and Antibody Fragments Following Systemic and Local Administration in Mice.

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmaceutics Pub Date : 2024-09-27 DOI:10.3390/pharmaceutics16101259
Prabhas Jagdale, Ashwni Verma, Dhaval K Shah
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Abstract

Objective: This study aimed to investigate the effect of molecular size on the pulmonary pharmacokinetics (PK) of proteins following systemic and local administration in wild-type mice. Methods: A non-cross-reactive antibody trastuzumab, and F(ab')2, Fab, and scFv fragments of this antibody were used for the investigation. Proteins were injected intravenously or via intratracheal instillation, and PK was measured in plasma, lungs, trachea, bronchi, and bronchoalveolar lavage (BAL) using ELISA. Concentrations in BAL were urea normalized. Results: Following systemic administration, the biodistribution coefficient (BC) for lungs, trachea, bronchi, and BAL was 11%, 11%, 15%, and 2% for the antibody; 15%, 7%, 13%, and 8% for F(ab')2; 25%, 17%, 28%, and 46% for Fab; and 14%, 1%, 2%, and 50% for scFv. The antibody exposure in BAL was ~50-fold lower than plasma and ~5-7-fold lower than lung tissues. A tissue-dependent BC vs. molecular size relationship was observed, where distribution in tissues was the highest for Fab (50 kDa), and scFv demonstrated the highest distribution in the BAL. PK data generated following local administration were quite variable; however, local dosing resulted in BAL exposures that were 10-100-fold higher than those achieved after systemic dosing for all proteins. The BAL antibody concentrations were 100-1000-fold higher than plasma concentrations initially, which normalized by day 14. For most proteins, local dosing resulted in higher lung concentrations than trachea and bronchi, opposite to what was observed after systemic dosing. Conclusions: The PK data presented here provide an unprecedented quantitative insight into the effect of molecular size on the pulmonary disposition of proteins following systemic and local administration.

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小鼠全身和局部给药后抗体和抗体片段的肺部药代动力学
研究目的本研究旨在探讨野生型小鼠全身和局部给药后,分子大小对蛋白质肺药代动力学(PK)的影响。研究方法研究使用了一种无交叉反应的抗体曲妥珠单抗以及该抗体的 F(ab')2、Fab 和 scFv 片段。蛋白质经静脉注射或气管内灌注,用酶联免疫吸附法测定血浆、肺、气管、支气管和支气管肺泡灌洗液(BAL)中的 PK 值。对 BAL 中的浓度进行了尿素归一化处理。结果:全身给药后,肺、气管、支气管和 BAL 的生物分布系数(BC)分别为:抗体 11%、11%、15% 和 2%;F(ab')2 15%、7%、13% 和 8% ;Fab 25%、17%、28% 和 46% ;scFv 14%、1%、2% 和 50% 。BAL 中的抗体暴露量比血浆低约 50 倍,比肺部组织低约 5-7 倍。观察到一种组织依赖性 BC 与分子大小的关系,其中 Fab(50 kDa)在组织中的分布最高,而 scFv 在 BAL 中的分布最高。局部用药后产生的 PK 数据变化很大;但是,对于所有蛋白,局部用药导致的 BAL 暴露量比全身用药后的暴露量高 10-100 倍。最初,BAL 中的抗体浓度是血浆浓度的 100-1000 倍,到第 14 天时浓度趋于正常。对于大多数蛋白质,局部用药导致肺部浓度高于气管和支气管,这与全身用药后观察到的情况相反。结论本文介绍的 PK 数据提供了前所未有的定量洞察力,让我们了解了分子大小对全身和局部给药后蛋白质肺部处置的影响。
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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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