AAPS Journal最新文献_第10页

Fabrication and Characterization of Antibody-Loaded Cationic Porous PLGA Microparticles for Sustained Antibody Release. 用于抗体持续释放的负载抗体的阳离子多孔PLGA微粒的制备和表征。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-22 DOI: 10.1208/s12248-023-00859-6

Ayaka Hanaki, Koki Ogawa, Tatsuaki Tagami, Tetsuya Ozeki

引用次数: 0

Phase-appropriate Application of Process Analytical Technology for Early Pharmaceutical Development of Oral Solid Dosage Forms-the Case Study of Uniformity Screening of Dosage Units and Blends. 过程分析技术在口服固体剂型早期药物开发中的阶段性应用——剂量单位和混合物均匀性筛选的案例研究。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-15 DOI: 10.1208/s12248-023-00854-x

Sayyeda Zeenat Razvi, Shengli Ma, Qiqing Zhong, Ariel Muliadi, Zhenqi Pete Shi

{"title":"Phase-appropriate Application of Process Analytical Technology for Early Pharmaceutical Development of Oral Solid Dosage Forms-the Case Study of Uniformity Screening of Dosage Units and Blends.","authors":"Sayyeda Zeenat Razvi, Shengli Ma, Qiqing Zhong, Ariel Muliadi, Zhenqi Pete Shi","doi":"10.1208/s12248-023-00854-x","DOIUrl":"10.1208/s12248-023-00854-x","url":null,"abstract":"Process analytical technology (PAT) in late-stage drug product development is typically used for real-time process monitoring, in-process control, and real-time release testing. In early research and development (R&D), PAT usage is limited as the manufacturing scale is relatively small with frequent changes and only a few batches are produced on an annual basis. However, process understanding is critical at early R&D in order to identify process and formulation boundaries, so PAT applications could be particularly useful in early-stage R&D. For oral solid dosage form, conventional HPLC-based content uniformity (CU) methods with sampling of 3 tablets per stratified sampling location in early R&D are typically not sufficient to identify these manufacturing process boundaries and temporal profile. Here, we report a screening CU method based on a multivariate model using transmission Raman spectroscopy (TRS) data on a phase-appropriate calibration set of only 16 tablets. This initial model was used for multiple pre-GMP development batches to provide critical information about blend uniformity and content uniformity (CU). In this work, the precision of the TRS method was evaluated; multiple spectral preprocessing approaches were compared regarding their effects on measurement precision as well as their ability to mitigate the photo bleaching effects during precision experiments. Overall, the TRS-based CU method was much faster than a traditional HPLC-based method allowing a much larger number of tablets to be screened. This larger number of analyzed tablets enabled the processes boundaries and temporal changes in CU to be identified while providing proper statistical assurance on product quality.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10287791","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 Case Study for Critical Reagent Qualification for Ligand Binding Assays Using Equivalence Test Methodology. 使用等效测试方法进行配体结合分析的关键试剂鉴定的案例研究。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-15 DOI: 10.1208/s12248-023-00857-8

Nancy A Niemuth, Cheryl A Triplett, Michael S Anderson, Karen A Sankovich, Thomas L Rudge

{"title":"A Case Study for Critical Reagent Qualification for Ligand Binding Assays Using Equivalence Test Methodology.","authors":"Nancy A Niemuth, Cheryl A Triplett, Michael S Anderson, Karen A Sankovich, Thomas L Rudge","doi":"10.1208/s12248-023-00857-8","DOIUrl":"10.1208/s12248-023-00857-8","url":null,"abstract":"Qualifying critical reagents in ligand binding assays by parallel testing of current and candidate reagent lots is recommended by regulatory agencies and industry groups, but specific guidance on the format of reagent qualification experiments is limited. Equivalence testing is a statistically sound approach that is consistent with the objective of critical reagent qualification. We present power analysis for equivalence regions ranging from 1.25- to 1.5-fold multiples of the GM ratio (centered on 1) of current and candidate lots, over a range of assay variability from 5 to 30% coefficient of variation (CV). A 1.25-fold equivalence region can be tested using 6 to 12 plates per lot for assays with up to 15% CV but is not practical for more variable assays. For these assays, wider equivalence regions are justified so long as care is taken to avoid assay drift and the assay remains suitable for the intended use. The equivalence test method is illustrated using historical data from passing and failing reagent qualification experiments. Simulation analysis was performed to support the design of qualification experiments using 6, 12, or 18 plates per lot over a broad range of assay variability. A challenge in implementing the equivalence test approach is selecting an appropriate equivalence region. Equivalence regions providing 90% power using 12 plates/lot were consistent with 1.5σ bounds, which are recommended for equivalence testing of critical quality attributes of biosimilars.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10288775","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

Ensemble Machine Learning Approaches Based on Molecular Descriptors and Graph Convolutional Networks for Predicting the Efflux Activities of MDR1 and BCRP Transporters. 基于分子描述符和图卷积网络的集成机器学习方法用于预测MDR1和BCRP转运蛋白的流出活性。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-12 DOI: 10.1208/s12248-023-00853-y

Asahi Adachi, Tomoki Yamashita, Shigehiko Kanaya, Yohei Kosugi

{"title":"Ensemble Machine Learning Approaches Based on Molecular Descriptors and Graph Convolutional Networks for Predicting the Efflux Activities of MDR1 and BCRP Transporters.","authors":"Asahi Adachi, Tomoki Yamashita, Shigehiko Kanaya, Yohei Kosugi","doi":"10.1208/s12248-023-00853-y","DOIUrl":"10.1208/s12248-023-00853-y","url":null,"abstract":"Multidrug resistance (MDR1) and breast cancer resistance protein (BCRP) play important roles in drug absorption and distribution. Computational prediction of substrates for both transporters can help reduce time in drug discovery. This study aimed to predict the efflux activity of MDR1 and BCRP using multiple machine learning approaches with molecular descriptors and graph convolutional networks (GCNs). In vitro efflux activity was determined using MDR1- and BCRP-expressing cells. Predictive performance was assessed using an in-house dataset with a chronological split and an external dataset. CatBoost and support vector regression showed the best predictive performance for MDR1 and BCRP efflux activities, respectively, of the 25 descriptor-based machine learning methods based on the coefficient of determination (R2). The single-task GCN showed a slightly lower performance than descriptor-based prediction in the in-house dataset. In both approaches, the percentage of compounds predicted within twofold of the observed values in the external dataset was lower than that in the in-house dataset. Multi-task GCN did not show any improvements, whereas multimodal GCN increased the predictive performance of BCRP efflux activity compared with single-task GCN. Furthermore, the ensemble approach of descriptor-based machine learning and GCN achieved the highest predictive performance with R2 values of 0.706 and 0.587 in MDR1 and BCRP, respectively, in time-split test sets. This result suggests that two different approaches to represent molecular structures complement each other in terms of molecular characteristics. Our study demonstrated that predictive models using advanced machine learning approaches are beneficial for identifying potential substrate liability of both MDR1 and BCRP.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10227862","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

Immunoinformatic Risk Assessment of Host Cell Proteins During Process Development for Biologic Therapeutics. 生物治疗过程开发过程中宿主细胞蛋白质的免疫信息学风险评估。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-11 DOI: 10.1208/s12248-023-00852-z

Kirk Haltaufderhyde, Brian J Roberts, Sundos Khan, Frances Terry, Christine M Boyle, Mitchell McAllister, William Martin, Amy Rosenberg, Anne S De Groot

引用次数: 0

Human Brain Penetration Prediction Using Scaling Approach from Animal Machine Learning Models. 利用动物机器学习模型的标度法预测人脑渗透。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-05 DOI: 10.1208/s12248-023-00850-1

Siyu Liu, Yohei Kosugi

{"title":"Human Brain Penetration Prediction Using Scaling Approach from Animal Machine Learning Models.","authors":"Siyu Liu, Yohei Kosugi","doi":"10.1208/s12248-023-00850-1","DOIUrl":"10.1208/s12248-023-00850-1","url":null,"abstract":"Machine learning (ML) approaches have been applied to predicting drug pharmacokinetic properties. Previously, we predicted rat unbound brain-to-plasma ratio (Kpuu,brain) by ML models. In this study, we aimed to predict human Kpuu,brain through animal ML models. First, we re-evaluated ML models for rat Kpuu,brain prediction by using trendy open-source packages. We then developed ML models for monkey Kpuu,brain prediction. Leave-one-out cross validation was utilized to rationally build models using a relatively small dataset. After establishing the monkey and rat ML models, human Kpuu,brain prediction was achieved by implementing the animal models considering appropriate scaling methods. Mechanistic NeuroPK models for the identical monkey and human dataset were treated as the criteria for comparison. Results showed that rat Kpuu,brain predictivity was successfully replicated. The optimal ML model for monkey Kpuu,brain prediction was superior to the NeuroPK model, where accuracy within 2-fold error was 78% (R2 = 0.76). For human Kpuu,brain prediction, rat model using relative expression factor (REF), scaled transporter efflux ratios (ERs), and monkey model using in vitro ERs can provide comparable predictivity to the NeuroPK model, where accuracy within 2-fold error was 71% and 64% (R2 = 0.30 and 0.52), respectively. We demonstrated that ML models can deliver promising Kpuu,brain prediction with several advantages: (1) predict reasonable animal Kpuu,brain; (2) prospectively predict human Kpuu,brain from animal models; and (3) can skip expensive monkey studies for human prediction by using the rat model. As a result, ML models can be a powerful tool for drug Kpuu,brain prediction in the discovery stage.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10217279","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

Anti-drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study. 使用信噪比（S/N）的抗药物抗体强度和临床相关性：博科昔单抗病例研究。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-09-02 DOI: 10.1208/s12248-023-00846-x

Fred McCush, Ellen Wang, Carla Yunis, Pamela Schwartz, Daniel Baltrukonis

{"title":"Anti-drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study.","authors":"Fred McCush, Ellen Wang, Carla Yunis, Pamela Schwartz, Daniel Baltrukonis","doi":"10.1208/s12248-023-00846-x","DOIUrl":"10.1208/s12248-023-00846-x","url":null,"abstract":"Historically, the biopharmaceutical industry has used titer to characterize the magnitude of an anti-drug antibody (ADA) response. While reporting levels of antibodies in terms of titer is generally understood and accepted by regulatory and medical communities, titer values are inherently variable given the multiple serial dilutions and reporting a value either directly before or interpolated at the assay cut point on the lower plateau of the assay curve range. Using S/N is an appealing alternative approach to titer as it simplifies analysis with less dilutions, significantly reducing testing, time, and resources and provides a more precise value potentially differentiating low-level ADA responses. Current bridging electrochemiluminescence (ECL) ADA assays using Meso Scale Discovery (MSD) platform are also significantly more sensitive and drug tolerant with wider assay ranges compared to historic ELISA platforms; therefore, ADA response based on S/N may help differentiate and identify those ADA samples that are more likely to be clinically relevant. Bococizumab is a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), which reduces plasma levels of low-density lipoprotein (LDL) cholesterol. Bococizumab was discontinued during Phase 3 clinical development based in part on the high rate of ADA and wide variation in LDL cholesterol responses among patients. The impact of anti-bococizumab antibodies on pharmacokinetic (PK) and pharmacodynamic (PD) endpoints was originally assessed using titer. Retrospective analysis of anti-bococizumab ADA responses using S/N ratios illustrates that S/N is an acceptable alternative to titer for characterizing the magnitude of ADA response and interpretation of clinically relevant ADA.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10207168","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: 1

Nature vs. Manmade: Comparing Exosomes and Liposomes for Traumatic Brain Injury. 自然与人造：比较外伤性脑损伤的外泌体和脂质体。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-08-23 DOI: 10.1208/s12248-023-00849-8

Kate Hennigan, Erin Lavik

{"title":"Nature vs. Manmade: Comparing Exosomes and Liposomes for Traumatic Brain Injury.","authors":"Kate Hennigan, Erin Lavik","doi":"10.1208/s12248-023-00849-8","DOIUrl":"10.1208/s12248-023-00849-8","url":null,"abstract":"Traumatic brain injury (TBI) of all severities is a significant public health burden, causing a range of effects that can lead to death or a diminished quality of life. Liposomes and mesenchymal stem cell-derived exosomes are two drug delivery agents with potential to be leveraged in the treatment of TBI by increasing the efficacy of drug therapies as well as having additional therapeutic effects. They exhibit several physical similarities, but key differences affect their performances as nanocarriers. Liposomes can be produced commercially at scale, and liposomes achieve higher encapsulation efficiency. Meanwhile, the intrinsic cargo and targeting moieties of exosomes, which liposomes lack, give exosomes a greater ability to facilitate neural regeneration, and exosomes do not trigger the infusion reactions that liposomes can. However, there are concerns about both exosomes and liposomes regarding interactions with tumors. The same routes of administration can be used for both exosomes and liposomes, resulting in somewhat different distribution throughout the body. While the effect of the nanocarrier type on accumulation in the brain is not concrete, targeting leads to increased accumulation of both exosomes and liposomes in the brain, upon which on-demand release can be used for both drug deliverers. Although neither have been applied to TBI in humans, preclinical trials have shown their immense potential, as have clinical trials pertaining to other brain injuries and conditions. While questions remain, research thus far shows that the various differences make exosomes a better choice of nanocarrier for TBI.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10127237","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: 1

Evolution of Antidrug Antibody Assays During the Development of Anti-Tissue Factor Pathway Inhibitor Monoclonal Antibody Marstacimab. 抗组织因子途径抑制剂单克隆抗体Marstacimab开发过程中抗药物抗体测定的进展。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-08-23 DOI: 10.1208/s12248-023-00847-w

Jean Donley, Darshana Jani, Tong Zhu, Yuhong Xiang, Boris Gorovits, Steven Arkin

{"title":"Evolution of Antidrug Antibody Assays During the Development of Anti-Tissue Factor Pathway Inhibitor Monoclonal Antibody Marstacimab.","authors":"Jean Donley, Darshana Jani, Tong Zhu, Yuhong Xiang, Boris Gorovits, Steven Arkin","doi":"10.1208/s12248-023-00847-w","DOIUrl":"10.1208/s12248-023-00847-w","url":null,"abstract":"Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic coagulation pathway. In patients with hemophilia A or B, inhibition of TFPI is an alternative therapeutic approach that augments the extrinsic coagulation pathway. Marstacimab is an investigational fully human monoclonal antibody that binds and neutralizes TFPI and is being evaluated as a prophylactic treatment to prevent or reduce the frequency of bleeding episodes in patients with severe hemophilia A or B, with or without inhibitors (antibodies against coagulation factors). However, the efficacy, safety, and pharmacokinetics of marstacimab may be affected by the induction of antidrug antibody (ADA) responses. Here, we describe the evolution and validation of three quasi-quantitative electrochemiluminescence-based methods to detect marstacimab ADAs, starting from their use in a first-in-human phase 1 study to their use in phase 2 and 3 clinical studies of patients with severe hemophilia. For all three methods, validation criteria evaluated the performance of the assays in screening and confirmatory cut points, precision, selectivity, drug tolerance, target interference, and stability. Additional criteria for validation were dilution linearity (Methods 1 and 2) and low positive control concentration, prozone effect, plate homogeneity, and robustness (Method 3). The three methods met validation criteria and are a potentially valuable tool in detecting the induction of marstacimab ADAs during treatment in patients with hemophilia.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10481779","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

Overcoming Soluble Target Interference in Measurement of Total Bispecific Therapeutic Antibody Concentrations. 克服测量总双特异性治疗性抗体浓度中的可溶性靶标干扰。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-08-18 DOI: 10.1208/s12248-023-00848-9

Jeongsup Shim, Jessica Chen, Montserrat Carrasco-Triguero, Saloumeh K Fischer

{"title":"Overcoming Soluble Target Interference in Measurement of Total Bispecific Therapeutic Antibody Concentrations.","authors":"Jeongsup Shim, Jessica Chen, Montserrat Carrasco-Triguero, Saloumeh K Fischer","doi":"10.1208/s12248-023-00848-9","DOIUrl":"10.1208/s12248-023-00848-9","url":null,"abstract":"The measurement of therapeutic drug concentrations is used to assess drug exposure and the relationship between therapeutic pharmacokinetics (PK) and pharmacodynamics (PD), which help determine the optimal dose for patients. Ligand binding assays (LBAs) are often the method of choice for evaluation of drug concentration and use either the therapeutic target protein or antibodies to the therapeutic as capture and/or detection reagents. Due to the bivalency of antibody therapeutics, heterogeneous states of the drug/target complex can exist in the presence of soluble targets which can complicate measurement of unbound drug. In the case of bispecific antibodies, measurement of drug can be even more complicated and depend upon the levels of both targets to each arm. Measuring the total drug allows for PKPD modeling prediction of human dose projections in addition to overcoming challenges associated with measuring free drug for bispecific antibodies. Here, we present a study in which a sandwich ELISA format was used to measure total anti-KLK5/KLK7 antibody concentrations. This assay utilized a non-blocking anti-idiotype (ID) antibody to one arm of the antibody for capture and an antibody to target bound to the other arm of the antibody for detection. Our qualified assay showed acceptable precision, accuracy, dilutional linearity, and reproducibility and enabled detection of a total bispecific antibody at high levels of two targets. To confirm that our assay was detecting total drug, a subset of samples was evaluated in a generic total LC-MS/MS assay.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10404080","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