AAPS Journal最新文献_第10页

Connexin-Containing Vesicles for Drug Delivery. 用于药物输送的含连接蛋白的囊泡

IF 4.5 3区医学

AAPS Journal Pub Date : 2024-01-24 DOI: 10.1208/s12248-024-00889-8

Mahmoud S Hanafy, Zhengrong Cui

引用次数: 0

Using Mechanistic Modeling Approaches to Support Bioequivalence Assessments for Oral Products. 使用机理建模方法支持口服产品的生物等效性评估。

IF 4.5 3区医学

AAPS Journal Pub Date : 2024-01-24 DOI: 10.1208/s12248-024-00886-x

Fang Wu, Youssef Mousa, Rebeka Jereb, Hannah Batchelor, Sumon Chakraborty, Tycho Heimbach, Ethan Stier, Filippos Kesisoglou, Sivacharan Kollipara, Lei Zhang, Liang Zhao

{"title":"Using Mechanistic Modeling Approaches to Support Bioequivalence Assessments for Oral Products.","authors":"Fang Wu, Youssef Mousa, Rebeka Jereb, Hannah Batchelor, Sumon Chakraborty, Tycho Heimbach, Ethan Stier, Filippos Kesisoglou, Sivacharan Kollipara, Lei Zhang, Liang Zhao","doi":"10.1208/s12248-024-00886-x","DOIUrl":"10.1208/s12248-024-00886-x","url":null,"abstract":"This report summarizes the proceedings for Day 1 Session 3 of the 2-day public workshop entitled \"Best Practices for Utilizing Modeling Approaches to Support Generic Product Development,\" a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) in the year 2022. The aims of this workshop were to discuss how to modernize approaches for efficiently demonstrating bioequivalence (BE), to establish their role in modern paradigms of generic drug development, and to explore and develop best practices for the use of modeling and simulation approaches in regulatory submissions and approval. The theme of this session is mechanistic modeling approaches supporting BE assessments for oral drug products. As a summary, with more successful cases of PBPK absorption modeling being developed and shared, the general strategies/frameworks on using PBPK for oral products are being formed; this will help further evolvement of this area. In addition, the early communications between the industry and the agency through appropriate pathways (e.g., pre-abbreviated new drug applications (pre-ANDA) meetings) are encouraged, and this will speed up the successful development and utility of PBPK modeling for oral products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"19"},"PeriodicalIF":4.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Screening Non-neutralizing Anti-idiotype Antibodies Against a Drug Candidate for Total Pharmacokinetic and Target Engagement Assay. 筛选针对候选药物的非中和抗原型抗体，用于总药效学和靶点参与测定。

IF 4.5 3区医学

AAPS Journal Pub Date : 2024-01-24 DOI: 10.1208/s12248-024-00892-z

Veronica Liu, Kelly McGrath, Josh Albert, Andrew P Mayer, Maria Busz, Mary Birchler, Huaping Tang, Yong Jiang

{"title":"Screening Non-neutralizing Anti-idiotype Antibodies Against a Drug Candidate for Total Pharmacokinetic and Target Engagement Assay.","authors":"Veronica Liu, Kelly McGrath, Josh Albert, Andrew P Mayer, Maria Busz, Mary Birchler, Huaping Tang, Yong Jiang","doi":"10.1208/s12248-024-00892-z","DOIUrl":"10.1208/s12248-024-00892-z","url":null,"abstract":"Non-neutralizing anti-idiotype antibodies against a therapeutic monoclonal antibody (mAb) play a crucial role in the creation of total pharmacokinetic (PK) assays and total target engagement (TE) assays during both pre-clinical and clinical development. The development of these anti-idiotype antibodies is challenging. In this study, we utilized a hybridoma platform to produce a variety of anti-idiotype antibodies against GSK2857914, a humanized IgG1 anti-BCMA monoclonal antibody. The candidate clones were evaluated using surface plasmon resonance (SPR) and bio-layer interferometry (BLI) for binding affinity, binding profiling, matrix interference, and antibody pairing determination. We discovered that three anti-idiotype antibodies did not prevent BCMA from binding to GSK2857914. All three candidates demonstrated high binding affinities. One of the three exhibited minimal matrix inference and could pair with the other two candidates. Additionally, one of the three clones was biotinylated as a capture reagent for the total PK assay, and another was labeled with ruthenium as a detection reagent for both the total PK assay and total TE assay. The assay results clearly show that these reagents are genuine non-neutralizing anti-idiotypic antibodies and are suitable for total PK and TE assay development. Based on this and similar studies, we conclude that the hybridoma platform has a high success rate for generating non-neutralizing anti-idiotype antibodies. Our methodology for developing and characterizing non-neutralizing anti-idiotype antibodies to therapeutic antibodies can be generally applied to any antibody-based drug candidate's total PK and total TE assay development.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"18"},"PeriodicalIF":4.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of Quantitative Comparative Approaches to Support Complex Generic Drug Development. 开发定量比较方法，支持复杂的仿制药开发。

IF 4.5 3区医学

AAPS Journal Pub Date : 2024-01-24 DOI: 10.1208/s12248-024-00885-y

Yuqing Gong, Francis-Xavier Barretto, Yi Tsong, Youssef Mousa, Ke Ren, Darby Kozak, Meiyu Shen, Meng Hu, Liang Zhao

{"title":"Development of Quantitative Comparative Approaches to Support Complex Generic Drug Development.","authors":"Yuqing Gong, Francis-Xavier Barretto, Yi Tsong, Youssef Mousa, Ke Ren, Darby Kozak, Meiyu Shen, Meng Hu, Liang Zhao","doi":"10.1208/s12248-024-00885-y","DOIUrl":"10.1208/s12248-024-00885-y","url":null,"abstract":"On October 27-28, 2022, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop titled \"Best Practices for Utilizing Modeling Approaches to Support Generic Product Development.\" This report summarizes the presentations and panel discussions for a session titled \"Development of Quantitative Comparative Approaches to Support Complex Generic Drug Development.\" This session featured speakers and panelists from both the generic industry and the FDA who described applications of advanced quantitative approaches for generic drug development and regulatory assessment within three main topics of interest: (1) API sameness assessment for complex generics, (2) particle size distribution assessment, and (3) dissolution profile similarity comparison. The key takeaways were that the analysis of complex data poses significant challenges to the application of conventional statistical bioequivalence methods, and there are various opportunities for using data analytics approaches for developing and applying suitable equivalence assessment method.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"15"},"PeriodicalIF":4.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Experience Learned and Perspectives on Using Model-Integrated Evidence in the Regulatory Context for Generic Drug Products-a Meeting Report. 关于在仿制药产品监管背景下使用模型综合证据的经验总结和观点--会议报告。

IF 4.5 3区医学

AAPS Journal Pub Date : 2024-01-10 DOI: 10.1208/s12248-023-00884-5

Eleftheria Tsakalozou, Lanyan Fang, Youwei Bi, Michiel van den Heuvel, Tausif Ahmed, Yu Chung Tsang, Robert Lionberger, Amin Rostami-Hodjegan, Liang Zhao

{"title":"Experience Learned and Perspectives on Using Model-Integrated Evidence in the Regulatory Context for Generic Drug Products-a Meeting Report.","authors":"Eleftheria Tsakalozou, Lanyan Fang, Youwei Bi, Michiel van den Heuvel, Tausif Ahmed, Yu Chung Tsang, Robert Lionberger, Amin Rostami-Hodjegan, Liang Zhao","doi":"10.1208/s12248-023-00884-5","DOIUrl":"10.1208/s12248-023-00884-5","url":null,"abstract":"This report summarizes relevant insights and discussions from a 2022 FDA public workshop titled Best Practices for Utilizing Modeling Approaches to Support Generic Product Development which illustrated how model-integrated evidence has been used and can be leveraged further to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA. The workshop attendees discussed that model-integrated evidence (MIE) approaches for generics are being applied in the space of long-acting injectable (LAI) products to develop shorter and more cost-effective alternative study designs for LAI products. Modeling and simulation approaches are utilized to support virtual BE assessments at the site of action for locally acting drug products and to assess the impact of food on BE assessments for oral dosage forms. The factors contributing to the success of the model-informed drug development program under PDUFA VI were discussed. The generic drug industry shared that decisions on formulation candidate/formulation variant selection, on pilot in vivo bioavailability studies, and on alternative study designs for BE assessment are informed by modeling and simulation approaches. There was agreement that interactions between the regulatory agencies and the industry are desirable because they improve the industry's understanding of scientific and other regulatory considerations on implementing modeling and simulation approaches in drug development and regulatory submissions.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"14"},"PeriodicalIF":4.5,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139418529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Building a Predictive PBPK Model for Human OATP Substrates: a Strategic Framework for Early Evaluation of Clinical Pharmacokinetic Variations Using Pitavastatin as an Example. 建立人类 OATP 底物的预测性 PBPK 模型：以匹伐他汀为例，早期评估临床药代动力学变异的战略框架。

IF 4.5 3区医学

AAPS Journal Pub Date : 2024-01-05 DOI: 10.1208/s12248-023-00882-7

Xiaomin Liang, Megan L Koleske, Jesse Yang, Yurong Lai

{"title":"Building a Predictive PBPK Model for Human OATP Substrates: a Strategic Framework for Early Evaluation of Clinical Pharmacokinetic Variations Using Pitavastatin as an Example.","authors":"Xiaomin Liang, Megan L Koleske, Jesse Yang, Yurong Lai","doi":"10.1208/s12248-023-00882-7","DOIUrl":"10.1208/s12248-023-00882-7","url":null,"abstract":"To select a drug candidate for clinical development, accurately and promptly predicting human pharmacokinetic (PK) profiles, assessing drug-drug interactions (DDIs), and anticipating potential PK variations in disease populations are crucial steps in drug discovery. The complexity of predicting human PK significantly increases when hepatic transporters are involved in drug clearance (CL) and volume of distribution (Vss). A strategic framework is developed here, utilizing pitavastatin as an example. The framework includes the construction of a monkey physiologically-based PK (PBPK) model, model calibration to obtain scaling factors (SF) of in vitro-in vivo extrapolation (IVIVE) for various clearance parameters, human model development and validation, and assessment of DDIs and PK variations in disease populations. Through incorporating in vitro human parameters and calibrated SFs from the monkey model of 3.45, 0.14, and 1.17 for CLint,active, CLint,passive, and CLint,bile, respectively, and together with the relative fraction transported by individual transporters obtained from in vitro studies and the optimized Ki values for OATP inhibition, the model reasonably captured observed pitavastatin PK profiles, DDIs and PK variations in human subjects carrying genetic polymorphisms, i.e., AUC within 20%. Lastly, when applying the functional reduction based on measured OATP1B biomarkers, the model adequately predicted PK changes in the hepatic impairment population. The present study presents a strategic framework for early-stage drug development, enabling the prediction of PK profiles and assessment of PK variations in scenarios like DDIs, genetic polymorphism, and hepatic impairment-related disease states, specifically focusing on OATP substrates.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"13"},"PeriodicalIF":4.5,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139106886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Use of the Same Model or Modeling Strategy Across Multiple Submissions: Focus on Complex Drug Products. 在多个申报材料中使用相同的模型或建模策略：关注复杂药物产品。

IF 4.5 3区医学

AAPS Journal Pub Date : 2024-01-04 DOI: 10.1208/s12248-023-00879-2

Ross L Walenga, Andrew H Babiskin, Sid Bhoopathy, James F Clarke, Jan De Backer, Murray Ducharme, Marc Kelly, Maxime Le Merdy, Miyoung Yoon, Partha Roy

{"title":"Use of the Same Model or Modeling Strategy Across Multiple Submissions: Focus on Complex Drug Products.","authors":"Ross L Walenga, Andrew H Babiskin, Sid Bhoopathy, James F Clarke, Jan De Backer, Murray Ducharme, Marc Kelly, Maxime Le Merdy, Miyoung Yoon, Partha Roy","doi":"10.1208/s12248-023-00879-2","DOIUrl":"10.1208/s12248-023-00879-2","url":null,"abstract":"Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"12"},"PeriodicalIF":4.5,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139099070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, Synthesis, and Biochemical Analysis of a Molecule Designed to Enhance Endosomal Escape. 设计、合成和生化分析旨在增强内体逃逸的分子。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-12-22 DOI: 10.1208/s12248-023-00876-5

Satish G Jadhav, Ryan L Setten, Carlos Medina, Xian-Shu Cui, Steven F Dowdy

{"title":"Design, Synthesis, and Biochemical Analysis of a Molecule Designed to Enhance Endosomal Escape.","authors":"Satish G Jadhav, Ryan L Setten, Carlos Medina, Xian-Shu Cui, Steven F Dowdy","doi":"10.1208/s12248-023-00876-5","DOIUrl":"10.1208/s12248-023-00876-5","url":null,"abstract":"RNA therapeutics, including siRNAs, ASOs, and PMOs, have great potential to treat human disease. However, RNA therapeutics are too large, too charged, and/or too hydrophilic to cross the cellular membrane and are instead taken up into cells by endocytosis. Unfortunately, the vast majority of RNA therapeutics remain trapped inside endosomes (≥ 99%), which is the sole reason preventing their use to treat cancer, COVID, and other diseases. In contrast, enveloped viruses, such as influenza, also have an endosomal escape problem, but have evolved a highly efficient endosomal escape mechanism using trimeric hemagglutinin (HA) fusogenic protein. HA contains an outer hydrophilic domain (HA1) that masks an inner hydrophobic fusogenic/endosomal escape domain (HA2). Once inside endosomes, HA1 is shed to expose HA2 that, due to hydrophobicity, buries itself into the endosomal lipid bilayer, driving escape into the cytoplasm in a non-toxic fashion. To begin to address the RNA therapeutics rate-limiting endosomal escape problem, we report here a first step in the design and synthesis of a universal endosomal escape domain (uEED) that biomimics the enveloped virus escape mechanism. uEED contains an outer hydrophilic mask covalently attached to an inner hydrophobic escape domain. In plasma, uEED is inert and highly metabolically stable; however, when placed in endo/lysosomal conditions, uEED is activated by enzymatic removal of the hydrophilic mask, followed by self-immolation of the linker resulting in exposure of the hydrophobic indole ring domain in the absence of any hydrophilic tags. Thus, uEED is a synthetic biomimetic of the highly efficient viral endosomal escape mechanism.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"10"},"PeriodicalIF":4.5,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138832776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quality of New Domestic Hand Sanitizer Drug Product Manufacturers During COVID-19. COVID-19 期间国内新洗手液药品制造商的质量。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-12-19 DOI: 10.1208/s12248-023-00877-4

Michelle Stafford, Rachel Linck Dunn, Nirzari Gupta, Raghavi Kakarla, Douglas Kirkpatrick, Daniel Magparangalan, Diem Ngo, Connie Gryniewicz-Ruzicka, Anjanette Smith, Matthew Stark, Wei Ye, Huzeyfe Yilmaz, Jeffrey Woodruff, Mary Manibusan, Neil Stiber, Alex Viehmann

{"title":"Quality of New Domestic Hand Sanitizer Drug Product Manufacturers During COVID-19.","authors":"Michelle Stafford, Rachel Linck Dunn, Nirzari Gupta, Raghavi Kakarla, Douglas Kirkpatrick, Daniel Magparangalan, Diem Ngo, Connie Gryniewicz-Ruzicka, Anjanette Smith, Matthew Stark, Wei Ye, Huzeyfe Yilmaz, Jeffrey Woodruff, Mary Manibusan, Neil Stiber, Alex Viehmann","doi":"10.1208/s12248-023-00877-4","DOIUrl":"10.1208/s12248-023-00877-4","url":null,"abstract":"The FDA initiated a cross-sectional, statistically based sampling and testing study to characterize the quality of marketed alcohol-based hand sanitizer (ABHS) by evaluating the alcohol content and impurities present in ABHS products manufactured by establishments that registered with the FDA during March-April 2020. A stratified sampling design divided the population of manufacturers into independent groups based on each establishment's level of experience with FDA oversight and its geographic location. ABHS products were collected and analyzed by spatially offset Raman spectroscopy and gas chromatography with mass spectrometry (GC-MS). The GC-MS results for 310 products, from 196 newly registered domestic manufacturers, showed that 71.6% (± 5.7%) of these manufacturers had violative products. In 104 (33.5%) cases, the alcohol content did not meet label claim assay specifications but still fell within CDC efficacy ranges. Ethanol ABHS products failed more often overall (assay and impurities) (84.3%) and for impurities (84.3%), than isopropanol ABHS products (11.2% and 6.2%, respectively). Differences in test results across active ingredients were statistically significant. Ethanol ABHS products often (63.5% of cases) failed due to the presence of acetal or acetaldehyde, particularly in products with pH ≤ 6. Other impurities were also detected in several ABHS products, suggesting the use of low-grade alcohol in the manufacture of these products. Evidence was insufficient to conclude that having experience manufacturing FDA-regulated products, or lack thereof, influenced product-level violative results. This study highlights the importance of sourcing and testing active pharmaceutical ingredients to produce quality drug products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"7"},"PeriodicalIF":4.5,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138813125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel Selective Quantification of Zinpentraxin Alfa Biotherapeutic in the Presence of Endogenous Isomer in Plasma Samples of Idiopathic Pulmonary Fibrosis Patients Using Immunoaffinity LC-MS. 利用免疫亲和力 LC-MS 对特发性肺纤维化患者血浆样本中存在内源性异构体的 Zinpentraxin Alfa 生物治疗药物进行新颖的选择性定量。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-12-19 DOI: 10.1208/s12248-023-00878-3

Maoyin Li, Audrey Arjomandi, Xiaowei Sun, Erhu Lu, Tulika Tyagi, WeiYu Lin, Saloumeh K Fischer, Surinder Kaur, Keyang Xu

{"title":"Novel Selective Quantification of Zinpentraxin Alfa Biotherapeutic in the Presence of Endogenous Isomer in Plasma Samples of Idiopathic Pulmonary Fibrosis Patients Using Immunoaffinity LC-MS.","authors":"Maoyin Li, Audrey Arjomandi, Xiaowei Sun, Erhu Lu, Tulika Tyagi, WeiYu Lin, Saloumeh K Fischer, Surinder Kaur, Keyang Xu","doi":"10.1208/s12248-023-00878-3","DOIUrl":"10.1208/s12248-023-00878-3","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease that affects three million patients worldwide and currently without an effective cure. Zinpentraxin alfa, a recombinant human pentraxin-2 (rhPTX-2) protein, has been evaluated as a potential drug candidate for the treatment of IPF. Clinical pharmacokinetic analysis of zinpentraxin alfa has been challenging historically due to interference from serum amyloid P component (SAP), an endogenous human pentraxin-2 protein. These molecules share an identical primary amino acid sequence and glycan composition; however, zinpentraxin alfa possesses α2,3-linked terminal sialic acid residues while SAP is an α2,6-linked isomer. By taking advantage of this only structural difference, we developed a novel assay strategy where α2,3-sialidase was used to selectively hydrolyze α2,3-linked sialic acid residues, resulting in desialylated zinpentraxin alfa versus unchanged sialylated SAP, following an immunoaffinity capture step. Subsequent tryptic digestion produced a unique surrogate asialo-glycopeptide from zinpentraxin alfa and allowed specific quantification of the biotherapeutic in human plasma. In addition, a common peptide shared by both molecules was selected as a surrogate to determine total hPTX-2 concentrations, i.e., sum of zinpentraxin alfa and SAP. The quantification methods for both zinpentraxin alfa and total hPTX-2 were validated and used in pharmacokinetic assessment in IPF patients. The preliminary results suggest that endogenous SAP levels remained largely constant in IPF patients throughout the treatment with zinpentraxin alfa. Our novel approach provides a general bioanalytical strategy to selectively quantify α2,3-sialylated glycoproteins in the presence of their corresponding α2,6-linked isomers.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"9"},"PeriodicalIF":4.5,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138813124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0