AAPS Journal最新文献_第3页

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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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

Neutralizing Antibody Sample Testing and Report Harmonization. 中和抗体样本检测与报告协调。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-12 DOI: 10.1208/s12248-024-00955-1

Darshana Jani, Michele Gunsior, Robin Marsden, Kyra J Cowan, Susan C Irvin, Laura Schild Hay, Bethany Ward, Luke Armstrong, Mitra Azadeh, Liching Cao, Rebecca Carmean, Jason DelCarpini, Sanjay L Dholakiya, Amanda Hays, Sarah Hosback, Zheng Hu, Nadia Kulagina, Seema Kumar, Ching Ha Lai, Marit Lichtfuss, Hsing-Yin Liu, Susana Liu, Reza Mozaffari, Luying Pan, Jason Pennucci, Marie-Eve Poupart, Gurleen Saini, Veerle Snoeck, Kristine Storey, Amy Turner, Inna Vainshtein, Daniela Verthelyi, Iwona Wala, Lili Yang, Lin Yang

{"title":"Neutralizing Antibody Sample Testing and Report Harmonization.","authors":"Darshana Jani, Michele Gunsior, Robin Marsden, Kyra J Cowan, Susan C Irvin, Laura Schild Hay, Bethany Ward, Luke Armstrong, Mitra Azadeh, Liching Cao, Rebecca Carmean, Jason DelCarpini, Sanjay L Dholakiya, Amanda Hays, Sarah Hosback, Zheng Hu, Nadia Kulagina, Seema Kumar, Ching Ha Lai, Marit Lichtfuss, Hsing-Yin Liu, Susana Liu, Reza Mozaffari, Luying Pan, Jason Pennucci, Marie-Eve Poupart, Gurleen Saini, Veerle Snoeck, Kristine Storey, Amy Turner, Inna Vainshtein, Daniela Verthelyi, Iwona Wala, Lili Yang, Lin Yang","doi":"10.1208/s12248-024-00955-1","DOIUrl":"10.1208/s12248-024-00955-1","url":null,"abstract":"Immunogenicity testing and characterization is an important part of understanding the immune response to administration of a protein therapeutic. Neutralizing antibody (NAb) assays are used to characterize a positive anti-drug antibody (ADA) response. Harmonization of reporting of NAb assay performance and results enables efficient communication and expedient review by industry and health authorities. Herein, a cross-industry group of NAb assay experts have harmonized NAb assay reporting recommendations and provided a bioanalytical report (BAR) submission editable template developed to facilitate agency filings. This document addresses key bioanalytical reporting gaps and provides a report structure for documenting clinical NAb assay performance and results. This publication focuses on the content and presentation of the NAb sample analysis report including essential elements such as the method, critical reagents and equipment, data analysis, study samples, and results. The interpretation of immunogenicity data, including the evaluation of the impact of NAb on safety, exposure, and efficacy, is out of scope of this publication.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592029","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

Knockout Transporter Cell Lines to Assess Substrate Potential Towards Efflux Transporters. 通过敲除转运体细胞系来评估外排转运体的底物潜能。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-10 DOI: 10.1208/s12248-024-00950-6

Donna A Volpe

{"title":"Knockout Transporter Cell Lines to Assess Substrate Potential Towards Efflux Transporters.","authors":"Donna A Volpe","doi":"10.1208/s12248-024-00950-6","DOIUrl":"10.1208/s12248-024-00950-6","url":null,"abstract":"P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance transporter 2 (MRP2) are efflux transporters involved in the absorption, excretion, and distribution of drugs. Bidirectional cell assays are recognized models for evaluating the potential of new drugs as substrates or inhibitors of efflux transporters. However, the assays are complicated by a lack of selective substrates and/or inhibitors, as well simultaneous expression of several efflux transporters in cell lines used in efflux models. This project aims to evaluate an in vitro efflux cell assay employing model substrates and inhibitors of P-gp, BCRP and MRP2 with knockout (KO) cell lines. The efflux ratios (ER) of P-gp (digoxin, paclitaxel), BCRP (prazosin, rosuvastatin), MRP2 (etoposide, olmesartan) and mixed (methotrexate, mitoxantrone) substrates were determined in wild-type C2BBe1 and KO cells. For digoxin and paclitaxel, the ER decreased to less than 2 in the cell lines lacking P-gp expression. The ER decreased to less than 3 for prazosin and less than 2 for rosuvastatin in the cell lines lacking BCRP expression. For etoposide and olmesartan, the ER decreased to less than 2 in the cell lines lacking MRP2 expression. The ER of methotrexate and mitoxantrone decreased in single- and double-KO cells without BCRP and MRP2 expression. These results show that KO cell lines have the potential to better interpret complex drug-transporter interactions without depending upon multi-targeted inhibitors or overlapping substrates. For drugs that are substrates of multiple transporters, the single- and double-KO cells may be used to assess their affinities for the different transporters.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565077","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

Intact NMR Approach Quickly Reveals Synchronized Microstructural Changes in Oil-in-Water Nanoemulsion Formulations. 完整核磁共振方法快速揭示水包油型纳米乳液配方中的同步微观结构变化

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-09 DOI: 10.1208/s12248-024-00945-3

Deyun Wang, Jiayi Li, Kang Chen

{"title":"Intact NMR Approach Quickly Reveals Synchronized Microstructural Changes in Oil-in-Water Nanoemulsion Formulations.","authors":"Deyun Wang, Jiayi Li, Kang Chen","doi":"10.1208/s12248-024-00945-3","DOIUrl":"10.1208/s12248-024-00945-3","url":null,"abstract":"A soft-core oil-in-water (o/w) nanoemulsion (NE) is composed of nanometer (nm) sized oil droplets, stabilized by a surfactant layer and dispersed in a continuous bulky water phase. Characterization of the o/w NE molecule arrangements non-invasively, particularly the drug phase distribution (DPD) and its correlation to oil globule size (OGS), remains a challenge. Here we demonstrated the analytical methods of intact 19F Nuclear Magnetic Resonance (NMR) and 1H diffusion ordered spectroscopy (DOSY) NMR for their specificity in measuring DPD and OGS, respectively, on three NE formulations containing the active ingredient difluprednate (DFPN) at the same concentration. The results illustrated synchronized molecular rearrangement reflected in the DPD and OGS upon alterations in formulation. Addition of surfactant resulted in a higher DPD in the surfactant layer, and concomitantly smaller OGS. Mechanic perturbation converted most of the NE globules to the smaller thermodynamically stable microemulsion (ME) globules, changing both DPD and OGS to ME phase. These microstructure changes were not observed using 1D 1H NMR; and dynamic light scattering (DLS) was only sensitive to OGS of ME globule in mechanically perturbed formulation. Collectively, the study illustrated the specificity and essential role of intact NMR methods in measuring the critical microstructure attributes of soft-core NE systems quickly, accurately, and non-invasively. Therefore, the selected NMR approach can be a unique diagnostic tool of molecular microstructure or Q3 property in o/w NE formulation development, and quality assurance after manufacture process or excipient component changes.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565061","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

Sample Size Determination and Study Design Impact on Dose-Scale Pharmacodynamic Bioequivalence: a Case Study Using Orlistat. 样本大小的确定和研究设计对剂量尺度药效生物等效性的影响：使用奥利司他的案例研究。

IF 5 3区医学

AAPS Journal Pub Date : 2024-07-03 DOI: 10.1208/s12248-024-00951-5

Lian Xu, Sanwang Li, Wei Wu, Zeneng Cheng, Feifan Xie

{"title":"Sample Size Determination and Study Design Impact on Dose-Scale Pharmacodynamic Bioequivalence: a Case Study Using Orlistat.","authors":"Lian Xu, Sanwang Li, Wei Wu, Zeneng Cheng, Feifan Xie","doi":"10.1208/s12248-024-00951-5","DOIUrl":"10.1208/s12248-024-00951-5","url":null,"abstract":"Dose-scale pharmacodynamic bioequivalence is recommended for evaluating the consistency of generic and innovator formulations of certain locally acting drugs, such as orlistat. This study aimed to investigate the standard methodology for sample size determination and the impact of study design on dose-scale pharmacodynamic bioequivalence using orlistat as the model drug. A population pharmacodynamic model of orlistat was developed using NONMEM 7.5.1 and utilized for subsequent simulations. Three different study designs were evaluated across various predefined relative bioavailability ratios of test/reference (T/R) formulations. These designs included Study Design 1 (2×1 crossover with T1 60 mg, R1 60 mg, and R2 120 mg), Study Design 2 (2×1 crossover with T2 120 mg, R1 60 mg, and R2 120 mg), and Study Design 3 (2×2 crossover with T1 60 mg, T2 120 mg, R1 60 mg, and R2 120 mg). Sample sizes were determined using a stochastic simulation and estimation approach. Under the same T/R ratio and power, Study Design 3 required the minimum sample size for bioequivalence, followed by Study Design 1, while Study Design 2 performed the worst. For Study Designs 1 and 3, a larger sample size was needed on the T/R ratio < 1.0 side for the same power compared to that on the T/R ratio > 1.0 side. The opposite asymmetry was observed for Study Design 2. We demonstrated that Study Design 3 is most effective for reducing the sample size for orlistat bioequivalence studies, and the impact of T/R ratio on sample size shows asymmetry.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499540","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