AAPS Journal最新文献_第10页

An Investigation of In Vitro Anti-Cancer Efficacy of Dihydroartemisinin-Loaded Bovine Milk Exosomes Against Triple-Negative Breast Cancer. 二氢青蒿素载体牛乳外泌体对三阴性乳腺癌的体外抗癌疗效研究

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-06 DOI: 10.1208/s12248-024-00958-y

Dulla Naveen Kumar, Aiswarya Chaudhuri, Udita Shiromani, Dinesh Kumar, Ashish Kumar Agrawal

{"title":"An Investigation of In Vitro Anti-Cancer Efficacy of Dihydroartemisinin-Loaded Bovine Milk Exosomes Against Triple-Negative Breast Cancer.","authors":"Dulla Naveen Kumar, Aiswarya Chaudhuri, Udita Shiromani, Dinesh Kumar, Ashish Kumar Agrawal","doi":"10.1208/s12248-024-00958-y","DOIUrl":"10.1208/s12248-024-00958-y","url":null,"abstract":"Repurposing drugs offers several advantages, including reduced time and cost compared to developing new drugs from scratch. It leverages existing knowledge about drug safety, dosage, and pharmacokinetics, expediting the process of clinical trials and regulatory approval. Dihydroartemisinin (DHA) is a semi-synthetic and active metabolite of all artemisinin molecules and is FDA-approved for the treatment of malaria. Apart from having anti-malarial properties, DHA also possesses anticancer properties. However, its pharmacological actions are limited by toxicity and solubility problems. To overcome these challenges and enhance its anticancer effectiveness, we designed an exosomal formulation of DHA. We isolated exosomes from bovine milk using differential ultracentrifugation and loaded DHA using sonication. Scanning and transition electron microscopy revealed a size of roughly 100 nm, with a spherical shape. Furthermore, in pH 7.4 and 5.5, the exosomes exhibited burst release followed by sustained release. Multiple in vitro cell culture tests demonstrated that Exo-DHA exhibited enhanced anticancer activity, including cytotoxicity, cellular uptake, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, and inhibition of colony formation. Additional evidence supporting Exo-DHA's anti-migration ability came from transwell migration and scratch assays. Based on these results, it was concluded that the anticancer efficacy of DHA was improved when loaded into bovine milk-derived exosomes. While the in vitro results are encouraging, more in vivo testing in suitable animal models and biochemical marker analysis are warranted.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"91"},"PeriodicalIF":5.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898902","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

Non-Invasive, Continuous, Quantitative Detection of Solvent Content in Vacuum Tray Drying. 无创、连续、定量检测真空托盘干燥过程中的溶剂含量。

IF 5 3区医学

AAPS Journal Pub Date : 2024-08-02 DOI: 10.1208/s12248-024-00944-4

Michel Y Louge, Jasdeep Mandur, Plamen Grigorov, William Blincoe, David Lamberto, Colton Bower, Robert F Meyer

引用次数: 0

A Data Driven Strategy and Case Study for Implementation of Singlicate Analysis in Ligand Binding Assays Used for PK Quantitation. 在用于 PK 定量的配体结合试验中实施单一分析的数据驱动策略和案例研究。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-31 DOI: 10.1208/s12248-024-00959-x

Qiang Qu, Susana Liu, Zhiping You, Gregory S Steeno, Lisa A Dyleski, Xue Mu, Ying Wang, Daniel Baltrukonis

{"title":"A Data Driven Strategy and Case Study for Implementation of Singlicate Analysis in Ligand Binding Assays Used for PK Quantitation.","authors":"Qiang Qu, Susana Liu, Zhiping You, Gregory S Steeno, Lisa A Dyleski, Xue Mu, Ying Wang, Daniel Baltrukonis","doi":"10.1208/s12248-024-00959-x","DOIUrl":"10.1208/s12248-024-00959-x","url":null,"abstract":"Duplicate analysis has been a conventional practice in the industry for ligand-binding assays (LBA), particularly for plate-based platforms like Enzyme-linked immunosorbent assay (ELISA) and Meso Scale Discovery (MSD) assays. Recent whitepapers and guidance have opened a door to exploring the implementation of single-well (singlicate) analysis approach for LBAs. Although the bioanalytical industry has actively investigated the suitability of singlicate analysis, applications in supporting regulated LBA bioanalysis are limited. The primary reason for this limitation is the absence of appropriate strategy to facilitate the transition from duplicate to singlicate analysis. In this paper we present the first case study with our data-driven approach to implement singlicate analysis in a clinical pharmacokinetics (PK) plate based LBA assay with ISR data. The central aspect of this strategy is a head-to-head comparison with Precision and Accuracy assessment in both duplicate and singlicate formats as the initial stage of assay validation. Subsequently, statistical analysis is conducted to evaluate method variability in both precision and accuracy. The results of our study indicated that there was no impactful difference between duplicate vs singlicate, affirming the suitability of singlicate analysis for the remaining steps of PK assay validation. The validation results obtained through singlicate analysis demonstrated acceptable assay performance characteristics across all validation parameters, aligning with regulatory guidance. The validated PK assay in singlicate has been employed to support a Phase I study. The appropriateness of singlicate analyses is further supported by initial Incurred Sample Reanalysis (ISR) data in which 90.1% of ISR samples fall within the acceptable criteria.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"88"},"PeriodicalIF":5.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861570","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

Recommendations for Development and Validation of a Fit-For-Purpose Biomarker Assays Using Western Blotting; An-AAPS Sponsored Initiative to Harmonize Industry Practices. 使用 Western 印迹法开发和验证适用于目的的生物标志物检测的建议；AAPS 赞助的协调行业实践的倡议。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-25 DOI: 10.1208/s12248-024-00946-2

Arvind Kinhikar, Mohamed Hassanein, Jake Harman, Catherine Soderstrom, Kimberly Honrine, Amy Lavelle, Marie-Anne Valentin, Joel Mathews

{"title":"Recommendations for Development and Validation of a Fit-For-Purpose Biomarker Assays Using Western Blotting; An-AAPS Sponsored Initiative to Harmonize Industry Practices.","authors":"Arvind Kinhikar, Mohamed Hassanein, Jake Harman, Catherine Soderstrom, Kimberly Honrine, Amy Lavelle, Marie-Anne Valentin, Joel Mathews","doi":"10.1208/s12248-024-00946-2","DOIUrl":"10.1208/s12248-024-00946-2","url":null,"abstract":"Western blot (WB) assays are routinely used for detection and quantification of biomarkers. Although assay validation to measure biomarkers in complex matrices has become a mainstay process for ligand binding assays (LBA) and mass spectrometry (MS), no guidelines exist yet validate biomarker methods using WB techniques. In this cross-industry white paper, we outlined in detail the key steps for development and for validation of WB assays for protein biomarkers under different contexts of use (COU). In addition, we described how to determine the level of assay validation needed for biomarker assays using Western blotting. For simplicity, we described two paths of WB assay validation. The first path (Path 1) is for biomarkers being analyzed for exploratory research or for internal go- or no/go- decision making. The second path (Path 2) is for clinical decision making such as dose determination or drug response that need to be run in a regulated environment. This work is supported through AAPS Biomarkers and Precision Medicine subteam and represents AAPS members opinion.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"87"},"PeriodicalIF":5.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767970","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

Evaluating the Performance of Two Automated Anti-drug Antibodies Assays for Infliximab and Adalimumab Without Acid Dissociation. 评估英夫利昔单抗和阿达木单抗两种无酸解离自动抗药抗体测定的性能

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-24 DOI: 10.1208/s12248-024-00953-3

Carley Karsten, Karin Grannas, Oskar Bergman, Robert Movérare, Matthew Roforth, Maria Alice V Willrich, Melissa R Snyder, Yifei K Yang

{"title":"Evaluating the Performance of Two Automated Anti-drug Antibodies Assays for Infliximab and Adalimumab Without Acid Dissociation.","authors":"Carley Karsten, Karin Grannas, Oskar Bergman, Robert Movérare, Matthew Roforth, Maria Alice V Willrich, Melissa R Snyder, Yifei K Yang","doi":"10.1208/s12248-024-00953-3","DOIUrl":"10.1208/s12248-024-00953-3","url":null,"abstract":"Monitoring anti-drug antibodies (ADAs) to infliximab and adalimumab is critical to treatment management in various autoimmune disorders. The growing need for proactive therapeutic monitoring further requires the detection of ADAs in the presence of measurable concentrations of infliximab or adalimumab. To provide robust analytical assays for clinical application, we evaluated two automated immunoassays developed using ImmunoCAP™ technology and based on the bridging format to measure serum ADAs to infliximab and adalimumab respectively. Without an acid-dissociation step, these research prototype assays can detect a positive control monoclonal ADA towards infliximab and adalimumab, ranging from < 25 ng/ml to 10,000 ng/mL. Both assays exhibit imprecision less than 20% at different ADA titer levels and can distinguish ADAs towards different drug targets. In method comparison using authentic patient samples, the quantitative results of the ADA assays are not directly comparable to two existing clinical immunoassays for ADAs (correlation coefficient rs = 0.673 for infliximab ADAs; rs = 0.510 for adalimumab ADAs), presumably due to the lack of commutable ADA standards and the polyclonal nature of ADAs. Nevertheless, there is qualitative agreement between the methods when evaluating putative positive and negative patient samples (overall agreement 0.83 for infliximab ADAs; 0.76 for adalimumab ADAs). Biotin and high levels of rheumatoid factors may interfere with the performance of the automated assays due to competitive binding with the biotinylated drug and non-specific formation of bridging complexes. The two ImmunoCAP assays can provide new analytical methods for proactive therapeutic monitoring of adalimumab and infliximab.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"86"},"PeriodicalIF":5.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753291","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

Evaluation of the Generic Drug User Fee Act (GDUFA) Program for Fiscal Years 2013-2022. 对 2013-2022 财政年度《非专利药品用户费法》（GDUFA）计划的评估。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-24 DOI: 10.1208/s12248-024-00948-0

Erica L Friedman, Leah W Falade, Michael G Bartlett

{"title":"Evaluation of the Generic Drug User Fee Act (GDUFA) Program for Fiscal Years 2013-2022.","authors":"Erica L Friedman, Leah W Falade, Michael G Bartlett","doi":"10.1208/s12248-024-00948-0","DOIUrl":"10.1208/s12248-024-00948-0","url":null,"abstract":"The effectiveness of the regulatory initiatives, strategies, and incentives put forth in the first two authorizations of the Generic Drug User Fees Act (GDUFA) were evaluated using factors including the number of Abbreviated New Drug Application (ANDA) withdrawals and first-cycle approvals. GDUFA was originally authorized in 2012 for FY 2013-2017 (GDUFA I) and reauthorized for FY 2018-2022 (GDUFA II). ANDA approvals were analyzed from the Drugs @ FDA database covering 2013-2022. From the applications, the approval time, dosage form and route of administration (ROA), product indication, market status of the product, first generic status, company and company size filing the ANDA were noted. Despite the COVID pandemic, there was more than a 40% increase in ANDA approvals during GDUFA II relative to GDUFA I. Oral and parenteral drugs were the two leading categories of approved generics during both iterations of GDUFA. There was more than a 120% increase in withdrawn applications during GDUFA II, which reflects the partial refund that is now offered to incentivize companies to withdraw inadequate applications prior to review. This also appears to have contributed to an increase in the number of first-cycle approvals, which increased by 100% between GDUFA I and II. Due to the COVID-19 public health emergency, there was a decrease in activity within the generic drug program and market. Therefore, it is important to consider this impact when observing actual trends from this study.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 5","pages":"85"},"PeriodicalIF":5.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753332","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

Immunogenicity of Atezolizumab: Influence of Testing Method and Sampling Frequency on Reported Anti-drug Antibody Incidence Rates. 阿特珠单抗的免疫原性：测试方法和抽样频率对报告的抗药抗体发生率的影响

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-15 DOI: 10.1208/s12248-024-00954-2

Maxime Usdin, Valerie Quarmby, James Zanghi, Coen Bernaards, Laura Liao, Joel Laxamana, Benjamin Wu, Steven Swanson, Yuan Song, Patty Siguenza

{"title":"Immunogenicity of Atezolizumab: Influence of Testing Method and Sampling Frequency on Reported Anti-drug Antibody Incidence Rates.","authors":"Maxime Usdin, Valerie Quarmby, James Zanghi, Coen Bernaards, Laura Liao, Joel Laxamana, Benjamin Wu, Steven Swanson, Yuan Song, Patty Siguenza","doi":"10.1208/s12248-024-00954-2","DOIUrl":"10.1208/s12248-024-00954-2","url":null,"abstract":"Measurement of anti-drug antibodies (ADA) to assess the incidence of ADA in a clinical trial is a critical step in immunogenicity assessment during the development of a protein therapeutic. We developed novel graphical approaches to illustrate clinical trial ADA data for the PD-L1 inhibitor atezolizumab (Tecentriq) that included a systematic analysis of the impact of the timing of ADA sampling and ADA assay drug tolerance on reported ADA incidence. We found that approaches used across the industry for ADA incidence analysis provide a limited view of immunogenicity in oncology studies, where ADA detection may be confounded by both drug dosage and patient attrition. Moreover, these approaches can miss important temporal information about the immune response. Our results demonstrated that the methodology of ADA assessment for the atezolizumab program was specifically designed to capture most ADA responses to ensure accurate reporting of ADA incidence. We further showed that the use of sparse sampling and/or ADA test methods with insufficient drug tolerance may result in a significant underreporting of ADA incidence. We conclude that the comparison of ADA incidence between different drugs can be highly misleading and that a test method with appropriate sensitivity in the presence of the drug and a clinical sampling scheme that is aligned with ADA responses to a drug is required to accurately report ADA incidence.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 4","pages":"84"},"PeriodicalIF":5.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621742","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

Effect of Physicochemical Properties on the Basic Drug-Acid-Polymer Interactions and Miscibility in PVA Based Orodispersible Films. 理化特性对基于 PVA 的可分散薄膜中基本药物-酸-聚合物相互作用和混溶性的影响

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-15 DOI: 10.1208/s12248-024-00949-z

Jie Liu, Yongguo Zhang, Chao Liu, Liang Fang

{"title":"Effect of Physicochemical Properties on the Basic Drug-Acid-Polymer Interactions and Miscibility in PVA Based Orodispersible Films.","authors":"Jie Liu, Yongguo Zhang, Chao Liu, Liang Fang","doi":"10.1208/s12248-024-00949-z","DOIUrl":"10.1208/s12248-024-00949-z","url":null,"abstract":"Salts of weakly basic drugs can partially dissociate in formulations, to give basic drugs and counter acids. The aim of the present study was to clarify the effect of physicochemical properties on the basic drug-acid-polymer interactions and salt-polymer miscibility, and to explain the influence mechanism at the molecular level. Six maleate salts with different physicochemical properties were selected and PVA was used as the film forming material. The relationship between the physicochemical properties and the miscibility was presented with multiple linear regression analysis. The existence state of salts in formulations were determined by XRD and Raman imaging. The stability of salts was characterized by NMR and XPS. The intermolecular interactions were investigated by FTIR and NMR. The results showed that the salt-PVA miscibility was related to polar surface area of salts and Tg of free bases, which represented hydrogen bond interaction and solubility potential. The basic drug-acid-PVA intermolecular interactions determined the existence state and bonding pattern of the three molecules. Meanwhile, the decrease of the stability after formulation increased the number of free bases in orodispersible films, which in turn affected the miscibility with PVA. The study provided references for the rational design of PVA based orodispersible films.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 4","pages":"83"},"PeriodicalIF":5.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621741","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

Kinetic Modeling for BT200 to Predict the Level of Plasma-Derived Coagulation Factor VIII in Humans. 建立 BT200 动力学模型，预测人体血浆衍生凝血因子 VIII 的水平。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-12 DOI: 10.1208/s12248-024-00952-4

Min-Soo Kim, Dagmar M Hajducek, James C Gilbert, Alfonso Iorio, Bernd Jilma, Andrea N Edginton

{"title":"Kinetic Modeling for BT200 to Predict the Level of Plasma-Derived Coagulation Factor VIII in Humans.","authors":"Min-Soo Kim, Dagmar M Hajducek, James C Gilbert, Alfonso Iorio, Bernd Jilma, Andrea N Edginton","doi":"10.1208/s12248-024-00952-4","DOIUrl":"10.1208/s12248-024-00952-4","url":null,"abstract":"Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 4","pages":"81"},"PeriodicalIF":5.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592028","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

Establishing Virtual Bioequivalence and Clinically Relevant Specifications for Omeprazole Enteric-Coated Capsules by Incorporating Dissolution Data in PBPK Modeling. 将溶出数据纳入 PBPK 模型，建立奥美拉唑肠溶胶囊的虚拟生物等效性和临床相关规范

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-12 DOI: 10.1208/s12248-024-00956-0

Ruwei Yang, Yaqi Lin, Kaifeng Chen, Jie Huang, Shuang Yang, An Yao, Xiaoyan Yang, Deqing Lei, Jing Xiao, Guoping Yang, Qi Pei

{"title":"Establishing Virtual Bioequivalence and Clinically Relevant Specifications for Omeprazole Enteric-Coated Capsules by Incorporating Dissolution Data in PBPK Modeling.","authors":"Ruwei Yang, Yaqi Lin, Kaifeng Chen, Jie Huang, Shuang Yang, An Yao, Xiaoyan Yang, Deqing Lei, Jing Xiao, Guoping Yang, Qi Pei","doi":"10.1208/s12248-024-00956-0","DOIUrl":"10.1208/s12248-024-00956-0","url":null,"abstract":"Currently, Biopharmaceutics Classification System (BCS) classes I and III are the only biological exemptions of immediate-release solid oral dosage forms eligible for regulatory approval. However, through virtual bioequivalence (VBE) studies, BCS class II drugs may qualify for biological exemptions if reliable and validated modeling is used. Here, we sought to establish physiologically based pharmacokinetic (PBPK) models, in vitro-in vivo relationship (IVIVR), and VBE models for enteric-coated omeprazole capsules, to establish a clinically-relevant dissolution specification (CRDS) for screening BE and non-BE batches, and to ultimately develop evaluation criteria for generic omeprazole enteric-coated capsules. To establish omeprazole's IVIVR based on the PBPK model, we explored its in vitro dissolution conditions and then combined in vitro dissolution profile studies with in vivo clinical trials. The predicted omeprazole pharmacokinetics (PK) profiles and parameters closely matched the observed PK data. Based on the VBE results, the bioequivalence study of omeprazole enteric-coated capsules required at least 48 healthy Chinese subjects. Based on the CRDS, the capsules' in vitro dissolution should not be < 28%-54%, < 52%, or < 80% after two, three, and six hours, respectively. Failure to meet these dissolution criteria may result in non-bioequivalence. Here, PBPK modeling and IVIVR methods were used to bridge the in vitro dissolution of the drug with in vivo PK to establish the BE safety space of omeprazole enteric-coated capsules. The strategy used in this study can be applied in BE studies of other BCS II generics to obtain biological exemptions and accelerate drug development.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 4","pages":"82"},"PeriodicalIF":5.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602124","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