Pharmaceutical Research最新文献

{"title":"Advances in Physiologically Based Pharmacokinetic (PBPK) Modeling and its Regulatory Utility to Support Oral Drug Product Development and Harmonization.","authors":"Yi-Hsien Cheng, Sherin Thomas, Yu Chung Tsang, Susana Almeida, Muhammad Ashraf, Nikoletta Fotaki, Tycho Heimbach, Nikunjkumar Patel, Harshil Shah, Xiaojian Jiang, Myong-Jin Kim, Rebecca Moody, Amin Rostami-Hodjegan, Romi Singh, Liang Zhao, Andrew Babiskin, Fang Wu","doi":"10.1007/s11095-025-03849-9","DOIUrl":"https://doi.org/10.1007/s11095-025-03849-9","url":null,"abstract":"<p><p>This report summarizes the proceedings of Session 1 of the one-day public workshop titled \"Advances in PBPK Modeling and its Regulatory Utility for Oral Drug Product Development\" hosted by the U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) on October 12, 2023. This report focuses on cutting-edge developments, ongoing challenges, and potential solutions in the field of physiologically based pharmacokinetic (PBPK) absorption modeling for systemic and gastrointestinal (GI) locally acting oral drug products, as well as exploring opportunities to enhance global harmonization for generic drug development. Despite significant advancements and several successful case studies of utilizing PBPK models in generic drug development, developing patient-centric dissolution quality standards using PBPK modeling that account for food effects or different disease states remains challenging. Combining multiple dissolution studies at different pH ranges can aid in developing patient-centric dissolution specifications. Additionally, a major challenge for GI locally acting drug products is the inability to validate the PBPK model for local bioavailability due to the lack of measured data for local drug concentration along the different sections of the GI tract. A totality of evidence-based approach, taking account of all available data in addition to PBPK modeling-based evidence, should be considered. Moving forward, it is crucial to promote global collaboration and research by sharing knowledge and experiences for utilizing PBPK models in regulatory contexts to advance both internal and international harmonization.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742562","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}

{"title":"PBPK Modeling to Support Bioavailability and Bioequivalence Assessment in Pediatric Populations.","authors":"Fang Wu, Eleftheria Tsakalozou, Gilbert J Burckart, Rebeka Žakelj, Lu Gaohua, Kazuko Sagawa, Viera Lukacova, Siva Vaithiyalingam, Jianghong Fan, Nikoletta Fotaki, Nikunjkumar Patel, Lanyan Fang","doi":"10.1007/s11095-025-03846-y","DOIUrl":"https://doi.org/10.1007/s11095-025-03846-y","url":null,"abstract":"<p><p>This report summarizes the proceedings for Session 3 of the one-day public workshop entitled \"Advances in PBPK Modeling and its Regulatory Utility for Oral Drug Product Development\" a jointly sponsored workshop by U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) on October 12, 2023. The theme of this session was the application and relevant considerations for PBPK modeling in supporting bioavailability (BA) and BE assessment in pediatric populations. The takeaway message from this session was that PBPK modeling can support relative BA and BE assessment in pediatrics since such studies are generally performed in adults or healthy subjects. PBPK absorption modeling can incorporate characteristics of the drug substance and formulation as well as pediatric physiology to assess the potential differences in absorption of different formulations in pediatrics for new and generic drugs. It is necessary to consider the totality of data and use all available evidence integrated into a mechanistic PBPK model to support decision-making. Global research efforts are needed to bridge critical data gaps.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720971","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}

{"title":"Predicting Distribution Coefficients (LogD) of Cyclic Peptides Using Molecular Dynamics Simulations.","authors":"Hao Lou, Mei Feng, Zahraa Al-Tamimi, Krzysztof Kuczera, Michael J Hageman","doi":"10.1007/s11095-025-03850-2","DOIUrl":"https://doi.org/10.1007/s11095-025-03850-2","url":null,"abstract":"<p><strong>Purpose: </strong>The distribution coefficient (LogD) is a critical property for oral peptide drug design. In this study, we focused on cyclic peptides (octreotide and its analogs) and aimed to determine their LogD values at four pHs using both the simulation and experimental approaches.</p><p><strong>Methods: </strong>For the experimental approach, the shake-flask method with LCMS quantification was employed to determine LogD values. For the simulation approach, the partition coefficient (LogP) was obtained from the solvation free energy calculations using molecular dynamics (MD) simulation. The LogD values were then calculated from the obtained LogP values considering the predicted pKa and ionization states of each peptide residue. More peptide properties such as polar surface area (PSA), number of intramolecular hydrogen bonds, solvent accessible surface area (SASA), and radius of gyration (R_g) were also calculated with the aid of MD simulation.</p><p><strong>Results: </strong>For a total of 28 LogD values across four pHs, the predicted values from the simulation under the OPLS-AA forcefield agreed with the experimental values, with an average deviation of 1.39 ± 0.86 log units, displaying better predictions compared to the data generated under the CHARMM forcefield or using commercial software. In addition, the analysis of PSA, SASA, and R_g data suggested the peptides exhibited some conformational flexibility in both aqueous and organic phases.</p><p><strong>Conclusions: </strong>The method developed in this study can predict the LogD values at a wide pH range covering multiple formulation/physiological conditions and therefore can provide insights into designing oral peptide drugs, especially for early-stage projects.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721000","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}

{"title":"GraphDeep-hERG: Graph Neural Network PharmacoAnalytics for Assessing hERG-Related Cardiotoxicity.","authors":"Yankang Jing, Yiyang Zhang, Guangyi Zhao, Terence McGuire, Jack Zhao, Ben Gibbs, Ganqian Hou, Zhiwei Feng, Ying Xue, Xiang-Qun Xie","doi":"10.1007/s11095-025-03848-w","DOIUrl":"https://doi.org/10.1007/s11095-025-03848-w","url":null,"abstract":"<p><strong>Purpose: </strong>The human Ether-a-go-go Related-Gene (hERG) encodes rectifying potassium channels that play a significant role during action potential repolarization of cardiomyocytes. Blockade of the hERG channel by off-target drugs can lead to long QT syndrome, significantly increasing the risk of proarrhythmic cardiotoxicity. Traditional hERG screening methods are effort-demanding and time-consuming. Thus, it is essential to develop computational methods to utilize the existing knowledge for faster and more accurate in silico screening. Although with wide use of deep learning/machine learning algorithms, existing computational models often rely on manually defined atomic features to represent atom nodes, which may overlook critical underlying information. Thus, we want to provide a new method to learn the atom representation automatically.</p><p><strong>Methods: </strong>We first developed an automated atom embedding model using deep neural networks (DNNs), trained with 118,312 compounds collected from the ZINC database. We then trained a Graph neural networks (GNNs) model with 7909 ChEMBL compounds as the classifying part. The integration of our atom embedding model and GNN models formed a classifier that could effectively distinguish between hERG inhibitors and non-inhibitors.</p><p><strong>Results: </strong>Our atom embedding model achieved 0.93 accuracy in representing structures. Our best GNN model achieved an accuracy of 0.84 and outcompeted traditional machine-learning models, as well as published AI-driven models, in external testing.</p><p><strong>Conclusions: </strong>These results highlight the potential of our automated atom embedding model as a standard for generating robust molecular representations. Its integration with advanced GNN algorithms offers promising assistance for screening hERG inhibitors and accelerating drug discovery and repurposing.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720968","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}

{"title":"Immunogenicity of Generic Peptide Impurities: Current Orthogonal Approaches.","authors":"Anne S De Groot, Aimee Mattei, Benjamin Gabriel, Jennifer Calderini, Brian J Roberts, Sandra Lelias, Mitchell McAllister, Christine Boyle, William Martin, Guilhem Richard","doi":"10.1007/s11095-025-03843-1","DOIUrl":"https://doi.org/10.1007/s11095-025-03843-1","url":null,"abstract":"<p><p>Generic drugs have saved consumers billions of dollars in the United States. The demand for lower-cost and effective drugs, particularly for well-known peptide drugs like Ozempic and Wegovy (brand names for semaglutide), has resulted in a surge of generic drug development to address perceived shortages in the supply of the reference listed drugs (RLD). To address this demand for generics and expedite consumer access to lower-cost generic versions of approved drugs, the U.S. Food and Drug Administration (FDA) has developed an \"Abbreviated New Drug Application\" (ANDA) pathway that simplifies the generic drug review process and expands access to these much-needed medicines without compromising quality and safety standards. Guidelines for this pathway require sponsors to identify and characterize both process- and product-related impurities in drug formulations that differ in nature or concentration from the RLD. The ANDA pathway devotes specific attention to immunogenicity and recommends the use of orthogonal methods of assessment to demonstrate that a proposed generic drug is immunologically equivalent to its RLD and therefore suitable for submission via the ANDA pathway. In this perspective, we describe several orthogonal methods for immunogenicity risk assessment of generic peptide impurities and contrast these with other methods such as MHC-Associated Peptide Proteomics peptide elution (MAPPs) assays. Given their importance in the generic drug approval pathway, we have submitted the \"PANDA^®\" immunogenicity risk assessment methods as a 'model master file'.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701146","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}

{"title":"Industry Perspectives on Implementation of Model Master File (MMF) Framework for Generics and Innovator Drugs: Opportunities, Challenges and Future Outlook.","authors":"Sivacharan Kollipara, Markus Friden, Tycho Heimbach, Pratik Saha, Jan De Backer, Tausif Ahmed, Timothy Nicholas","doi":"10.1007/s11095-025-03844-0","DOIUrl":"10.1007/s11095-025-03844-0","url":null,"abstract":"<p><p>Modeling and simulation (M&S) based approaches have proven significant utility in both new drug and generic product development. Considering the plethora of applications of such novel approaches, the concept of model master file (MMF) has been introduced recently to streamline the regulatory submission process as well as to facilitate the use of M&S approaches. The MMF has potential to reduce the applicant's efforts in preparing and submitting modeling-based applications and can result in reduced review timelines. Approved MMF's are considered as reusable, sharable, portable and generalizable and thus can be used by the same applicant in multiple submissions or by multiple applicants. To further increase the understanding of the MMF framework and to understand potential applications, and limitations, the USFDA and the Center for Research on Complex Generics (CRCG, https://www.complexgenerics.org ) co-hosted a hybrid public workshop titled \"Considerations and Potential Regulatory Applications for a Model Master File\". This article summarizes the industry perspectives of MMF implementation from both new drug and generic product development perspectives. With the help of diverse case studies, an effort was made in the manuscript to discuss potential challenges, opportunities and benefits. The objective of this article is to portray industry thinking on the MMF concept and the use and implementation of the concept during drug discovery and development. The views presented in this manuscript are of industry participants present at the workshop and not the industry at large.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616762","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}

{"title":"Considering Opportunities and Challenges When Implementing the Model Master File Framework - a Meeting Report.","authors":"Eleftheria Tsakalozou, Lanyan Fang, Erin Skoda, Timothy Nicholas, Sivacharan Kollipara, Ke Ren, Stella Grosser, Bhagwant Rege, Partha Roy, Hao Zhu, Liang Zhao","doi":"10.1007/s11095-025-03839-x","DOIUrl":"https://doi.org/10.1007/s11095-025-03839-x","url":null,"abstract":"","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586664","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}

{"title":"Considerations for Regulatory Reusability of Dynamic Tools in the New Drug Development.","authors":"Jiang Liu, Yuching Yang, Joga Gobburu, Cynthia J Musante, Martin Klein, Liang Zhao, Rajanikanth Madabushi, Hao Zhu","doi":"10.1007/s11095-025-03831-5","DOIUrl":"https://doi.org/10.1007/s11095-025-03831-5","url":null,"abstract":"<p><p>Model-informed drug development (MIDD) approaches have become indispensable for new drug development and to address regulatory challenges. Dynamic tools, such as population pharmacokinetics (popPK), physiologically-based pharmacokinetics (PBPK), and quantitative systems pharmacology (QSP) models, are routinely employed to enhance the efficiency of drug development. Recently, the Fit-for-Purpose (FFP) initiative and the Model Master File (MMF) framework have emerged to support model reusability and sharing in regulatory settings. In this manuscript we share key insights from the Session \"Pathways for Regulatory Acceptance of Dynamic Tools in the New Drug Space\" of Workshop \"Considerations and Potential Regulatory Applications for a Model Master File\", hosted by the U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) and discuss the considerations for regulatory acceptance of dynamic modeling tools. Presentations at the workshop explored current practices in PBPK model evaluation, the potential for popPK models in bioequivalence (BE) assessments, and the implications of reusing models. Challenges such as context-specific validation, version control, and the impact of scientific and technological advancements on model reuse were emphasized. The workshop underscored the importance of clear regulatory pathways and structured frameworks for the consistent application of reusable models. The MMF's potential to streamline reviews and reduce redundancies was noted, although operational details require further elaboration. Continued collaboration among stakeholders is essential to refine model-sharing practices, enhance model validation processes, and promote transparency, ensuring that MIDD approaches remain robust and adaptable to evolving regulatory needs.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557671","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}

{"title":"Population Pharmacokinetics of IV Lidocaine and its Metabolites in Adult Surgical Patients.","authors":"Keng Wah Foong, Pui San Loh, Sook Hui Chaw, Yoke Lin Lo","doi":"10.1007/s11095-025-03835-1","DOIUrl":"10.1007/s11095-025-03835-1","url":null,"abstract":"<p><strong>Background: </strong>Perioperative lidocaine infusions show potential as a systemic analgesic and to enhance postoperative recovery. This study characterised the pharmacokinetics (PK) of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in adult surgical patients using non-linear mixed-effects modelling.</p><p><strong>Methods: </strong>Thirty-four donor nephrectomy and 64 cholecystectomy patients received intraoperative IV lidocaine. Plasma samples were collected perioperatively and analysed in NONMEM. Covariate effects and alternative dosing regimens were investigated.</p><p><strong>Results: </strong>1,520 concentration-timepoints were analysed. Lidocaine PK was best fitted with a 3-compartment model, while MEGX and GX used a 2-compartment model. All parameters were scaled allometrically with total body mass and fat-free mass (FFM). Lidocaine had a typical clearance of 45.9 L/h, decreasing by 60% postoperatively, and a central volume of 25.2 L. Peripheral compartments 1 and 2 exhibited intercompartmental clearances of 142 L/h and 5.81 L/h, with volumes of 44.4 L and 29.3 L, respectively. Peripheral compartment 1's volume expanded with intraoperative fluid administration. Simulations suggested an FFM-based dosing regimen (bolus: 2.5 mg/kg over 30 min, single infusion: 2 mg/kg over 1 h, maintenance infusion: 1.5 mg/kg/h) quickly achieved and maintained a lidocaine target plasma concentration of 1.5 mg/L.</p><p><strong>Conclusions: </strong>The joint parent-metabolites model adequately describes the disposition of lidocaine and its metabolites, incorporating allometric scaling and key covariates. It provides a foundation for optimising lidocaine dosing and guiding investigations to establish target plasma concentrations for safe and effective use in the general surgical population. Further research is warranted to refine and evaluate the model's utility in other surgical populations.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"451-473"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531751","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}

{"title":"Phytochemicals and their Nanoformulations for Overcoming Drug Resistance in Head and Neck Squamous Cell Carcinoma.","authors":"Zhai Pingping, Chen Nan, Tang Yong","doi":"10.1007/s11095-025-03836-0","DOIUrl":"10.1007/s11095-025-03836-0","url":null,"abstract":"<p><strong>Background: </strong>Drug resistance remains a significant challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), leading to therapeutic failure and poor patient prognosis. Numerous mechanisms, including drug efflux pumps, altered tumor microenvironment (TME), and dysregulated cell death pathways, contribute to the development of resistance against conventional chemotherapeutic agents, immunotherapy, and targeted therapies. As resistance to traditional treatments continues to emerge, there is an urgent need for innovative therapeutic strategies to overcome these challenges. Phytochemicals are naturally occurring bioactive compounds and have demonstrated remarkable potential in targeting multiple resistance mechanisms simultaneously.</p><p><strong>Method: </strong>This review comprehensively overviews the current understanding of drug resistance mechanisms in HNSCC and explores innovative strategies utilizing phytochemicals and their nanoformulations to overcome these resistance mechanisms, with a particular focus on recent developments and future perspectives in this field.</p><p><strong>Results and discussion: </strong>Phytochemicals with anticancer properties include a wide range of herbal-derived molecules such as flavonoids, stilbenes, curcuminoids, alkaloids, traditional Chinese medicine, and others. These compounds can modulate ATP-binding cassette transporters, reverse epithelial-to-mesenchymal transition (EMT), target cancer stem cells (CSCs), and regulate various signaling pathways involved in drug resistance. The integration of phytochemicals into advanced nanoformulation systems has also shown a remarkable improvement in enhancing their bioavailability, stability, and targeted delivery to the TME, potentially improving their therapeutic efficacy. Furthermore, the combination of phytochemicals with conventional chemotherapeutic agents, targeted molecular therapy, and immune checkpoint inhibitors (ICIs) has exhibited synergistic effects, offering a promising approach to restoring drug sensitivity in resistant HNSCC cells.</p><p><strong>Conclusion: </strong>Phytochemicals and their nanoformulations may improve response of HNSCC to therapy by alleviating drug resistance.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"429-449"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542977","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}