{"title":"Pulmonary Pharmacokinetics of Antibody and Antibody Fragments Following Systemic and Local Administration in Mice.","authors":"Prabhas Jagdale, Ashwni Verma, Dhaval K Shah","doi":"10.3390/pharmaceutics16101259","DOIUrl":null,"url":null,"abstract":"<p><p><b>Objective:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusions:</b> 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.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"16 10","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11510323/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/pharmaceutics16101259","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
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.
PharmaceuticsPharmacology, 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.