AAPS Journal最新文献_第6页

Enhancing Efavirenz Bioavailability Via Polymer-Based Buccal Administration: Optimization and Characterization of Nanocrystal-Loaded Dissolving Microneedle Delivery Systems. 通过基于聚合物的口腔给药提高依非韦伦的生物利用度：纳米晶体负载溶解微针给药系统的优化与表征。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01047-4

Khairiyah Khairiyah, Muh Bisfain Asaf, Nur Afni Annisa Achmad, Rachmatya W Tuna, Irfan Kurniawan, Anugerah Yaumil Ramadhani Aziz, Maria Mir, Juan Domínguez-Robles, Mónica Millán-Jiménez, Ilyas Essadki-Aittaji, Ana B Cobo-González, Muhammad Aswad, Latifah Rahman, Marianti A Manggau, Aliyah Aliyah, Eyman Mohamed Eltayib, Andi Dian Permana

{"title":"Enhancing Efavirenz Bioavailability Via Polymer-Based Buccal Administration: Optimization and Characterization of Nanocrystal-Loaded Dissolving Microneedle Delivery Systems.","authors":"Khairiyah Khairiyah, Muh Bisfain Asaf, Nur Afni Annisa Achmad, Rachmatya W Tuna, Irfan Kurniawan, Anugerah Yaumil Ramadhani Aziz, Maria Mir, Juan Domínguez-Robles, Mónica Millán-Jiménez, Ilyas Essadki-Aittaji, Ana B Cobo-González, Muhammad Aswad, Latifah Rahman, Marianti A Manggau, Aliyah Aliyah, Eyman Mohamed Eltayib, Andi Dian Permana","doi":"10.1208/s12248-025-01047-4","DOIUrl":"10.1208/s12248-025-01047-4","url":null,"abstract":"Efavirenz (EFV) is a widely utilized antiretroviral agent in HIV/AIDS therapy that is known for its efficacy but is also associated with various side effects. For improved drug delivery, buccal administration offers a promising alternative by allowing the drug to enter the systemic circulation directly through the oral mucosa, bypassing the gastrointestinal tract and first-pass metabolism. This study explored the interaction between EFV and different polymers through molecular docking, revealing a strong binding affinity to Pluronic®F-127 (-2.1 kcal/mol). EFV was formulated into nanocrystals (EFV-NC) using Pluronic®F-127 as the stabilizer, characterized by an average particle size of 174.83 ± 15.21 nm, a narrow size distribution (PDI of 0.15 ± 0.013), and good stability (zeta potential of -22.27 ± 1.12 mV). FTIR and XRD analyses revealed polymer-induced alterations in the crystalline structure of the EFV. The EFV-NC formulation enhanced the solubility (up to 400 µg/mL) and achieved 89.58 ± 4.01% drug release within 24 h, following the Higuchi model kinetics for controlled release. EFV-NC-loaded dissolving microneedles (EFV-NC-DMN) demonstrated robust mechanical properties, efficient tissue penetration, and minimal moisture absorption. Ex vivo and in vivo studies revealed that compared with oral EFV, EFV-NC-DMN provided a relative bioavailability of 137.40%, with higher plasma concentrations and prolonged release, highlighting its potential for superior HIV/AIDS management via buccal administration and improved therapeutic outcomes.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"64"},"PeriodicalIF":5.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634813","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

Therapeutic Drug Monitoring of Biologics: Current Practice, Challenges and Opportunities - a Workshop Report. 生物制剂治疗药物监测：当前实践，挑战和机遇-研讨会报告。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01050-9

Sophie Shubow, Michele Gunsior, Amy Rosenberg, Yow-Ming Wang, Tara Altepeter, Daphne Guinn, Mohsen Rajabiabhari, Joseph Kotarek, Diane R Mould, Honghui Zhou, Adam S Cheifetz, Sandra Garces, Rachel Chevalier, Sean Gavan, Mark R Trusheim, Theo Rispens, Kurtis Bray, Michael A Partridge

{"title":"Therapeutic Drug Monitoring of Biologics: Current Practice, Challenges and Opportunities - a Workshop Report.","authors":"Sophie Shubow, Michele Gunsior, Amy Rosenberg, Yow-Ming Wang, Tara Altepeter, Daphne Guinn, Mohsen Rajabiabhari, Joseph Kotarek, Diane R Mould, Honghui Zhou, Adam S Cheifetz, Sandra Garces, Rachel Chevalier, Sean Gavan, Mark R Trusheim, Theo Rispens, Kurtis Bray, Michael A Partridge","doi":"10.1208/s12248-025-01050-9","DOIUrl":"10.1208/s12248-025-01050-9","url":null,"abstract":"Therapeutic drug monitoring (TDM) for dose modification of biologics has the potential to improve patient outcomes. The US Food and Drug Administration (FDA) and the American Association of Pharmaceutical Scientists (AAPS) hosted the first US-based public workshop on TDM of biologics with contributions from a broad array of interested parties including healthcare providers, clinical pharmacologists, test developers, bioanalysis and immunogenicity scientists, health economics and outcomes research (HEOR) experts and regulators. The key insight was that despite a body of evidence to support TDM in certain therapeutic areas, there remain substantial challenges to widespread clinical implementation. There is a lack of consensus regarding the integration of TDM in clinical guidelines, and a lack of consensus on the cost-effectiveness of TDM; both factors contribute to the difficulty that healthcare providers face in obtaining reimbursement for TDM (both coverage of testing itself, and coverage of potential dosing modifications). The HEOR experts outlined alternative routes to obtaining reimbursement and suggested advocating for changes in coverage policies to promote TDM use in the clinic. Reaching alignment across policy makers, patients and advocacy groups, payers, and healthcare providers, on specific treatment settings where TDM will be clearly beneficial, was identified as an important step to advancing TDM implementation for the benefit of patients.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"62"},"PeriodicalIF":5.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634734","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

A Facile Way to Enhance the Therapeutic Efficacy of Hydrophobic Drugs via Amorphous Solid Dispersions. 一种通过非晶固体分散体提高疏水药物疗效的简便方法。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01046-5

Ning Tao, Zihui Yan, Xin Wang, Yuhui Wang, Li Ji, Lin Qiu, Pengfei Cui, Jianhao Wang

{"title":"A Facile Way to Enhance the Therapeutic Efficacy of Hydrophobic Drugs via Amorphous Solid Dispersions.","authors":"Ning Tao, Zihui Yan, Xin Wang, Yuhui Wang, Li Ji, Lin Qiu, Pengfei Cui, Jianhao Wang","doi":"10.1208/s12248-025-01046-5","DOIUrl":"10.1208/s12248-025-01046-5","url":null,"abstract":"Approximately 40% of marketed drugs and 75% of invested drugs in the pharmaceutical field are poorly soluble hydrophobic drugs with minimal solubility in water which make them difficult to be absorbed by the body and significantly limiting their applications. Among chemotherapeutic agents, numerous antitumor drugs such as platinum compounds, camptothecin, paclitaxel and others are also restricted in processing and preparation due to solubility issues. Therefore, improving the solubility and enhancing the therapeutic efficacy of drugs have always been significant research topics in current pharmaceutics. Herein, we propose an amorphous solid dispersion system PRTA-DOX, involving the protein drug protamine sulphate and hydrophobic doxorubicin as the model hydrophobic drug. In previous studies, ASD (Amorphous Solid Dispersion) has been demonstrated to enhance the solubility of hydrophobic drugs and result in a storage-stable system. Protamine sulphate as a marketed drug is reliable in safety and conveniently obtained. Doxorubicin, an antitumor drug with a broad antitumor spectrum, is commonly used in the treatment of breast cancer. Typically, doxorubicin is prepared in the form of a hydrochloride salt to increase its solubility. However, the utilization of doxorubicin hydrochloride is reduced due to drug resistance issues in biological cells and it exhibits higher toxicity to the body. In this system, protamine sulphate which is rich in arginine guanidino hydrophobic planes physically mixes with doxorubicin which is a hydrophobic molecule with aromatic rings and they are connected through weak interactions: π-π conjugation. They constitute an amorphous solid dispersion system which increases the solubility of hydrophobic doxorubicin, enhances cellular uptake, mitigate some cellular drug resistance and thereby achieves the purpose of improving therapeutic efficacy.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"63"},"PeriodicalIF":5.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634810","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

Characterizing the Hepatic Metabolic Pathway of Ketone Ester and Subsequent Metabolites Using Human and Rat Liver Fractions. 用人和大鼠肝脏组织表征酮酯及其代谢产物的肝脏代谢途径。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01044-7

N Panse, P M Gerk

{"title":"Characterizing the Hepatic Metabolic Pathway of Ketone Ester and Subsequent Metabolites Using Human and Rat Liver Fractions.","authors":"N Panse, P M Gerk","doi":"10.1208/s12248-025-01044-7","DOIUrl":"10.1208/s12248-025-01044-7","url":null,"abstract":"Although exogenous ketogenic dietary supplements continue to grow in popularity, their pharmacokinetic properties have not been adequately studied, thus hindering their optimal use and benefits. Here, the metabolic characteristics of one such supplement (Veech ketone mono-ester ((R)-3-hydroxybutyl(R)-3-hydroxybutyrate) (KE)) were studied along with its metabolite- (R)-1,3-butanediol ((R)-1,3-BD), both of which are precursors and undergo metabolic conversion to (R)-beta-hydroxybutyrate (BHB). The metabolism of aldol (an aldehyde intermediate between the conversion of (R)-1,3-BD to (R)-BHB was also evaluated, as it is frequently not considered in any scientific discussion. The metabolic parameters were calculated using pooled human (mixed gender) and pooled rat (male and female) liver fractions. These were later used to estimate the hepatic extraction ratio and the hepatic clearance of these molecules. KE showed rapid and non-saturable clearance in human and rat liver fractions, even at concentrations as high as 15,000 μM. In the case of (R)-1,3-BD, there was saturable metabolism in rats and humans with Km and Vmax values of 8,000 μM and 27.1 nmol/min/mg of protein (humans), 19,300 μM and 113.5 nmol/min/mg of protein (male rats), and 11,910 μM and 75.8 nmol/min/mg of protein (female rats). The metabolism of aldol showed rapid and non-saturable hepatic clearance in human liver fractions.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"65"},"PeriodicalIF":5.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634812","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

The Role of Enhanced Analytical Procedure Development in Facilitating Post-Approval Changes Via Established Conditions. 加强分析程序开发在通过既定条件促进批准后变更中的作用。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01037-6

Douglas Kirkpatrick, Nirzari Gupta, Ramesh Gopalaswamy, Rohit Kolhatkar, Morgan Hudson-Davis, David Keire

{"title":"The Role of Enhanced Analytical Procedure Development in Facilitating Post-Approval Changes Via Established Conditions.","authors":"Douglas Kirkpatrick, Nirzari Gupta, Ramesh Gopalaswamy, Rohit Kolhatkar, Morgan Hudson-Davis, David Keire","doi":"10.1208/s12248-025-01037-6","DOIUrl":"10.1208/s12248-025-01037-6","url":null,"abstract":"Enabling greater flexibility for lifecycle management of analytical procedures is one of the primary features of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q12 Lifecycle Management guideline. Rather than rely on a comparatively slower and burdensome post-approval change supplement process, ICH Q12 created a new pathway to facilitate changes to chemistry, manufacturing, and controls. The new framework utilized key concepts such as established conditions (ECs), post-approval change management protocols, and the product lifecycle management document to allow modifications to analytical procedures based upon pre-approved conditions. Shortly after the publication of ICH Q12, the ICH Q14 Analytical Procedure Development guideline provided further guidance on how knowledge gained during analytical procedure development could be incorporated with the ICH Q12 framework to support scientifically sound and risk-based post-approval changes. However, to date, the full potential of ICH Q12 and Q14 remains unrealized, likely due to uncertainty over how analytical procedure development data can be effectively utilized to gain regulatory flexibility for post-approval changes. In this case study, an example of determining, proposing, and justifying analytical procedure ECs, reporting categories, and identification of elements not considered ECs is presented. In addition, how such information could be presented in a regulatory submission is described. Importantly, this case study serves as an example of the application of ICH Q12 and Q14 principles for analytical procedures, but it is not intended to serve as official guidance nor to define the full scope of information required in a regulatory submission.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"61"},"PeriodicalIF":5.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634732","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

PBPK Modeling to Recommend Nevirapine Dosing in HIV and HIV-TB Co-infected Patients: Leveraging Enzyme Auto-Induction, Drug Interactions, and Ethnic Variability. PBPK模型在HIV和HIV- tb合并感染患者中推荐奈韦拉平剂量：利用酶自身诱导、药物相互作用和种族差异

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-12 DOI: 10.1208/s12248-025-01042-9

Xuexin Ye, Feiyan Liu, Zeneng Cheng, Feifan Xie

{"title":"PBPK Modeling to Recommend Nevirapine Dosing in HIV and HIV-TB Co-infected Patients: Leveraging Enzyme Auto-Induction, Drug Interactions, and Ethnic Variability.","authors":"Xuexin Ye, Feiyan Liu, Zeneng Cheng, Feifan Xie","doi":"10.1208/s12248-025-01042-9","DOIUrl":"10.1208/s12248-025-01042-9","url":null,"abstract":"Nevirapine, primarily metabolized by CYP2B6 and CYP3A4, exhibits enzyme auto-induction and significant ethnic variability in its pharmacokinetics (PK). These complexities are further exacerbated in HIV-TB co-infected patients, where nevirapine is often co-administered with rifampicin/isoniazid-based anti-tuberculosis (TB) therapies. Rifampicin, a strong CYP3A4 inducer and moderate CYP2B6 inducer, and isoniazid, a moderate CYP3A4 inhibitor, create intricate drug interactions that challenge optimal nevirapine dosing strategies, leading to clinical uncertainty and debate. We developed a physiologically based pharmacokinetic (PBPK) model for nevirapine that integrates auto-induction, drug interactions, and ethnic variability. The model successfully captured the time-dependent PK of nevirapine across Caucasian, African, and Asian populations, with and without rifampicin/isoniazid co-administration. Simulations revealed that the standard nevirapine regimen (200 mg QD lead-in, 200 mg BID maintenance) was appropriate for Caucasian and African HIV patients but required adjustment to 150 mg QD lead-in and 150 mg BID maintenance for Asians to minimize toxicity. In HIV-TB co-infected patients, nevirapine co-administration with rifampicin/isoniazid was unsuitable for Caucasians due to sub-therapeutic levels. For Africans, an increased regimen (200 mg QD lead-in, 300 mg BID maintenance) was recommended, while drug interactions did not alter the reduced dosing recommendation of nevirapine for Asians. Our findings underscore the necessity of incorporating ethnic variability and drug interaction profiles into nevirapine dosing strategies to optimize therapeutic efficacy and safety in HIV and HIV-TB co-infected patients.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"59"},"PeriodicalIF":5.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617774","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

Uniform Spray Dried Loxapine Microparticles Potentially for Nasal Delivery: Exploring Discriminatory In Vitro Release Evaluation Methods. 均匀喷雾干燥洛沙平微颗粒可能用于鼻腔给药：探索歧视性体外释放评价方法。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-12 DOI: 10.1208/s12248-025-01045-6

Mengyuan Li, Ziwei Nie, Shen Yan, Shengyu Zhang, Xiao Dong Chen, Winston Duo Wu

{"title":"Uniform Spray Dried Loxapine Microparticles Potentially for Nasal Delivery: Exploring Discriminatory In Vitro Release Evaluation Methods.","authors":"Mengyuan Li, Ziwei Nie, Shen Yan, Shengyu Zhang, Xiao Dong Chen, Winston Duo Wu","doi":"10.1208/s12248-025-01045-6","DOIUrl":"10.1208/s12248-025-01045-6","url":null,"abstract":"This study aimed to develop suitable in vitro evaluation methods for the release behavior of nasal powders (NPs). We synthesized a range of standardized microparticles with adjustable size and morphology by co-spray-drying loxapine succinate (LOX) and gelatin (GEL) using an ethanol/water solvent mixture in a self-designed micro-fluidic jet spray dryer (MFJSD). The influence of the LOX/GEL mass ratio and solvent composition on particle characteristics, including size, morphology, and crystalline properties, was systematically investigated. In vitro release profiles of NPs were thoroughly assessed across different release medium, apparatus, and membranes. The modified Transwell® system, utilizing simulated nasal electrolyte solution (SNES) as the release medium, was identified as the most effective in distinguishing the performance of microparticles with diverse attributes. Furthermore, the impact of particle size, morphology, and crystalline properties on in vitro release profiles was discussed. This research presents a robust methodology for the in vitro evaluation of NPs release profiles and provides a practical approach for the rational fabrication of high-quality NPs products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"60"},"PeriodicalIF":5.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617775","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

Best Practices and Recommendations for Non-Liquid Matrices Bioanalysis. 非液体基质生物分析的最佳实践和建议。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-11 DOI: 10.1208/s12248-025-01033-w

Faye Vazvaei-Smith, Wenkui Li, Omar S Barnaby, Sanjeev Bhardwaj, Juyao Dong, Carolyne Dumont, Carmen Fernández-Metzler, Brian Geist, Mohamed Hassanein, Amanda Hays, Anna Ilinskaya, Eugene P Kadar, Kris King, Nadia Kulagina, Murali K Matta, Krishna Midde, Rina Pan, Divya Pathania, Thomas Tarnowski, Eric Tewalt, Eric Thomas, Enaksha Wickremsinhe, Deqing Xiao

{"title":"Best Practices and Recommendations for Non-Liquid Matrices Bioanalysis.","authors":"Faye Vazvaei-Smith, Wenkui Li, Omar S Barnaby, Sanjeev Bhardwaj, Juyao Dong, Carolyne Dumont, Carmen Fernández-Metzler, Brian Geist, Mohamed Hassanein, Amanda Hays, Anna Ilinskaya, Eugene P Kadar, Kris King, Nadia Kulagina, Murali K Matta, Krishna Midde, Rina Pan, Divya Pathania, Thomas Tarnowski, Eric Tewalt, Eric Thomas, Enaksha Wickremsinhe, Deqing Xiao","doi":"10.1208/s12248-025-01033-w","DOIUrl":"10.1208/s12248-025-01033-w","url":null,"abstract":"The analysis of Non-Liquid Matrices (NLMs) can provide key information on many aspects in drug discovery and development. These include but are not limited to drug uptake and distribution, engagement and modulation, and target exposure. A thorough understanding of these aspects is fundamental to the progression of drug development. In many cases, such an understanding can only be achieved through quantitative analysis of NLMs. Such dependence can lead to bottlenecks in the drug development process-as the practices and regulations that govern bioanalysis of conventional liquid matrices typically cannot be directly applied to NLMs. This paper strives to fill this crucial gap. To this end, subject matter experts from across the industry, through the auspices of the AAPS Bioanalytical Community, have combined their collective best practices for NLM bioanalysis in this paper. Certainly, this endeavor came with challenges, the most prominent of which also serves as the impetus for this project, the lack of literature on NLM bioanalysis dealing with different types of NLM, analysis rigor, and best practices to draw from. This paper aims to serve as a comprehensive set of best practices drawn from the experiences of leading scientists across the industry-for NLM bioanalysis in drug development.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"57"},"PeriodicalIF":5.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607060","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

Functional Activity and Binding Specificity of Small Ankyrin Repeat Proteins Called Ankyrons Against SARS-CoV-2 Variants. 被称为锚蛋白的小锚蛋白重复蛋白对SARS-CoV-2变体的功能活性和结合特异性

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-11 DOI: 10.1208/s12248-025-01043-8

Yun-Jong Park, Wojciech Jankowski, Nicholas C Hurst, Jeremy W Fry, Nikolai F Schwabe, Linda C C Tan, Zuben E Sauna

{"title":"Functional Activity and Binding Specificity of Small Ankyrin Repeat Proteins Called Ankyrons Against SARS-CoV-2 Variants.","authors":"Yun-Jong Park, Wojciech Jankowski, Nicholas C Hurst, Jeremy W Fry, Nikolai F Schwabe, Linda C C Tan, Zuben E Sauna","doi":"10.1208/s12248-025-01043-8","DOIUrl":"10.1208/s12248-025-01043-8","url":null,"abstract":"Effective management of COVID-19 requires clinical tools to treat the disease in addition to preventive vaccines. Several recombinant mAbs and their cocktails have been developed to treat COVID-19 but these have limitations. Here, we evaluate small ankyrin repeat proteins called Ankyrons that were generated to bind with high affinity to the SARS-CoV-2 virus. Ankyrons are ankyrin repeat proteins comprised of repetitions a structural module. Each module consists of a β-turn followed by two antiparallel α-helices. The Ankyrons™ are directly selected in vitro from a highly diverse library of around a trillion clones in ribosome display and like antibodies can bind with high affinity to almost any target. We assessed Ankyrons that were generated against the wild-type SARS-CoV-2 and the Delta (B.1.617.2) and Omicron (BA.1) variants in a binding assay. We determined that all Ankyrons were specific in that they did not bind to MERS. While all Ankyrons bound with high affinity to the variant they were generated against, some also showed cross-reactivity to all three SARS-CoV-2 variants. Binding assays are useful for screening analytes but do not provide information about clinical effectiveness. Therefore, we used a pseudovirus-based neutralization assay to show that five of the Ankyrons evaluated neutralized all three strains of SARS-CoV-2. We have provided a workflow for the evaluation of novel Ankyrons against a viral target. This suggests that Ankyrons could be useful for rapidly developing new research tools for studying other emerging infectious diseases rapidly with the optional further potential for developing Ankyrons into diagnostic and even therapeutic applications.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"58"},"PeriodicalIF":5.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607072","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

A Phase-Appropriate Risk Assessment Strategy in Support of the Safety of Peptide and Oligonucleotide-Related Impurities. 支持多肽和寡核苷酸相关杂质安全性的阶段适宜风险评估策略。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-06 DOI: 10.1208/s12248-025-01023-y

Brian W Pack, Robert W Siegel, Paul D Cornwell, Andrea Ferrante, Douglas A Roepke, Michael E Hodsdon, Laurent Malherbe, Mark A Carfagna

{"title":"A Phase-Appropriate Risk Assessment Strategy in Support of the Safety of Peptide and Oligonucleotide-Related Impurities.","authors":"Brian W Pack, Robert W Siegel, Paul D Cornwell, Andrea Ferrante, Douglas A Roepke, Michael E Hodsdon, Laurent Malherbe, Mark A Carfagna","doi":"10.1208/s12248-025-01023-y","DOIUrl":"10.1208/s12248-025-01023-y","url":null,"abstract":"There is limited regulatory guidance that outlines the globally acceptable level of individual and total impurities present in peptide and oligonucleotide drug substances that can be supported and accepted during clinical testing. In early clinical development, there is uncertainty regarding the potential toxicological and immunogenicity risk of these impurities relative to the active pharmaceutical ingredient; however, as pharmaceutical development companies move closer to marketing applications, this uncertainty lessens through knowledge gained by clinical and toxicology studies. While these peptide and oligonucleotide related impurities are predicted to be under process control and to have the same safety profile as the parent drug substance, they do not offer any inherent advantages to the patient. Thus, the safety and specification control of these impurities is frequently challenged by regulatory agencies. In support of phase-appropriate control strategies, this manuscript presents a risk-based approach to evaluate the safety of peptide and oligonucleotide impurities from a toxicology and immunogenicity perspective. In many cases, the proposed safety threshold is higher than what is accepted by regulatory bodies, but still is expected to be safe based upon sound toxicological principles which should be the focus for clinical studies. The risk assessment strategies presented here consider the stage of development, indication, potential impact of unintended cross reactivity with endogenous proteins, dose, and frequency of dosing throughout development to inform chemistry manufacturing and control of inherent safety risks associated with API-related impurities. Importantly, for the first time, this manuscript establishes a threshold of immunogenicity concern along with an experimental mitigation plan specifically for peptide impurities as a function of the development phase.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"56"},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574594","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