The AAPS Journal最新文献

Evaluating AlphaFold for Clinical Pharmacology and Pharmacogenetics: A Case-Study of Huntingtin Variants Linked to Huntington’s Disease 为临床药理学和药物遗传学评估 AlphaFold：与亨廷顿氏症有关的亨廷廷基因变异的案例研究

The AAPS Journal Pub Date : 2024-09-17 DOI: 10.1208/s12248-024-00969-9

Ajith Kumar Ethirajulu, Vineesh Sriramoju, Amruta Gajanan Bhat, Murali Ramanathan

{"title":"Evaluating AlphaFold for Clinical Pharmacology and Pharmacogenetics: A Case-Study of Huntingtin Variants Linked to Huntington’s Disease","authors":"Ajith Kumar Ethirajulu, Vineesh Sriramoju, Amruta Gajanan Bhat, Murali Ramanathan","doi":"10.1208/s12248-024-00969-9","DOIUrl":"https://doi.org/10.1208/s12248-024-00969-9","url":null,"abstract":"To evaluate the artificial intelligence (AI)-guided AlphaFold algorithm for studying the binding interactions of human huntingtin and the aggregation of huntingtin peptides. Variants of huntingtin protein implicated in Huntington’s disease were used as a model system to evaluate AlphaFold. Variants of huntingtin and huntingtin peptides with polyglutamine tracts (PQT) containing 21, 31, 51, or 78 glutamines were studied. The 3-dimensional structures of huntingtin variants and their interactions with huntingtin-associated protein-40 (HAP40) were obtained. Aggregation experiments were conducted with peptide sequences corresponding to variants of PQT, amino terminal sequence (NTS) plus PQT, NTS plus PQT plus proline rich region (PRR), and the 300 amino acid sequence from the NTS through HEAT3 of huntingtin. Oligomerization experiments with 1, 3, 6, or 12 peptide sequences were used to assess the quaternary structures of aggregates. The PQT and PQT plus NTS peptides formed a helical secondary structure that formed a central core in the quaternary structure of the aggregates The PRR formed an extended type II polyproline helix that did not participate in central core the aggregates. The distance between the amino and carboxyl termini of disease-linked 31Q, 51Q, and 78Q variants of full-length huntingtin was prominently decreased compared to the 21Q huntingtin. The interaction of HAP40 with the 78Q variant increased the distance between the amino and carboxyl termini. AlphaFold identified key tertiary structure changes in human huntingtin that have been independently corroborated in experimental models. The results highlight the utility of AlphaFold for hypothesis generation in pharmaceutical research.","PeriodicalId":501692,"journal":{"name":"The AAPS Journal","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142248585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Determining the Degree of Sulfo-tag Conjugation to AAV5 Vectors by LC-HRMS and Evaluating the Effects on Antibody Binding Affinity and Bridging Assay Sensitivity 通过 LC-HRMS 确定 AAV5 载体的磺酸标签共轭程度并评估其对抗体结合亲和力和桥接测定灵敏度的影响

The AAPS Journal Pub Date : 2024-09-16 DOI: 10.1208/s12248-024-00970-2

Yanshan Dai, Xinqun Wu, Xiaowei Sun, Daniel Cohen, Divakar Rajeswaran, Scott Robotham, Shannon Chilewski, Kun Yang, Graham Yearwood, Alexander Kozhich, Vibha Jawa

{"title":"Determining the Degree of Sulfo-tag Conjugation to AAV5 Vectors by LC-HRMS and Evaluating the Effects on Antibody Binding Affinity and Bridging Assay Sensitivity","authors":"Yanshan Dai, Xinqun Wu, Xiaowei Sun, Daniel Cohen, Divakar Rajeswaran, Scott Robotham, Shannon Chilewski, Kun Yang, Graham Yearwood, Alexander Kozhich, Vibha Jawa","doi":"10.1208/s12248-024-00970-2","DOIUrl":"https://doi.org/10.1208/s12248-024-00970-2","url":null,"abstract":"Pre-existing anti-AAV antibodies can be detected using ligand binding-based assay formats. One such format is the MSD-based bridging assay, which uses sulfo-tag-labeled AAV vectors as detection reagents. However, no method has been developed to accurately measure the degree of sulfo-tag labeling on AAV vectors. To fill this gap, we developed a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method to assess the degree of labeling (DoL) of sulfo-tag on AAV5 vectors, enabling the measurement of the DoL on AAV5 at six increasing levels of sulfo-tag challenge ratio. In addition, a Biacore-based assay was used to evaluate the binding affinity between an anti-AAV5 monoclonal antibody and various sulfo-tag labeled AAV5 vectors. The results indicated that increased DoL of sulfo-tag labeling on AAV5 did not compromise the binding affinity.Our study further employed the MSD-bridging assay to detect the binding Signal/Noise (S/N) ratios of four anti-AAV5 monoclonal antibodies (mAbs) to various sulfo-tag-labeled AAV5 vectors. The findings revealed a strong correlation between the degree of sulfo-tag labeling and both the S/N ratios and the sensitivity of MSD bridging assays. This result underscores the importance of optimizing the labeling of detection reagents to enhance assay sensitivity for detecting anti-AAV5 antibodies.<h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":501692,"journal":{"name":"The AAPS Journal","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142248582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Planning Split-Apheresis Designs for Demonstrating Comparability of Cellular and Gene Therapy Products 为证明细胞和基因治疗产品的可比性而规划分隔设计

The AAPS Journal Pub Date : 2024-09-16 DOI: 10.1208/s12248-024-00977-9

Richard Burdick, Jeff Hofer, Andrew Karl, Heath Rushing

引用次数: 0

ICH M10 Bioanalytical Method Validation Guideline-1 year Later ICH M10 生物分析方法验证指南-1 年后

The AAPS Journal Pub Date : 2024-09-12 DOI: 10.1208/s12248-024-00974-y

Faye Vazvaei-Smith, Enaksha Wickremsinhe, Eric Woolf, Chongwoo Yu

引用次数: 0

Design of Auto-Adaptive Drug Delivery System for Effective Delivery of Peptide Drugs to Overcoming Mucus and Epithelial Barriers 设计自动适应性给药系统，克服粘液和上皮屏障，有效输送多肽药物

The AAPS Journal Pub Date : 2024-09-12 DOI: 10.1208/s12248-024-00971-1

Ruihuan Ding, Yanping Li, Wei Zheng, Yiying Sun, Zhenyu Zhao, Houqian Zhang, Ranran Yuan, Aiping Wang, Kaoxiang Sun, Hongbo Wang, Yanan Shi

{"title":"Design of Auto-Adaptive Drug Delivery System for Effective Delivery of Peptide Drugs to Overcoming Mucus and Epithelial Barriers","authors":"Ruihuan Ding, Yanping Li, Wei Zheng, Yiying Sun, Zhenyu Zhao, Houqian Zhang, Ranran Yuan, Aiping Wang, Kaoxiang Sun, Hongbo Wang, Yanan Shi","doi":"10.1208/s12248-024-00971-1","DOIUrl":"https://doi.org/10.1208/s12248-024-00971-1","url":null,"abstract":"Oral administration of peptide represents a promising delivery route, however, it is hindered by the harsh gastrointestinal environment, leading to low in vivo absorption. In this study, auto-adaptive protein corona-AT 1002-cationic liposomes (Pc-AT-CLs) are constructed with the characteristic of hydrophilic and electrically neutral surface properties for the encapsulation of liraglutide. BSA protein corona is used to coat AT-CLs reducing the adherence of mucus, and may fall off after penetrating the mucus layer. Transmucus transport experiment demonstrated that the mucus penetration amount of Pc-AT-CLs are 1.45 times that of AT-CLs. After penetrating the mucus layer, AT-CLs complete transmembrane transport by the dual action of AT and cationic surface properties. Transmembrane transport experiment demonstrated that the apparent permeability coefficient (Papp) of AT-CLs is 2.03 times that of CLs. In vivo tests demonstrated that Pc-AT-CLs exhibited a significant hypoglycemic effect and enhanced the relative bioavailability comparing to free liraglutide. Pc-AT-CLs protect liraglutide from degradation, facilitate its absorption, and ultimately improve its oral bioavailability.<h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>In this study, AT-CLs (AT-1002 peptide attached to cationic liposomes) and coated with BSA (bovine serum albumin) together form Pc-AT-CLs. The purpose of simultaneously improved mucus permeating ability and transepithelial absorption. When the carrier penetrates the mucus, the BSA protein corona coating may fall off. Then, AT-CLs carriers possessing cationic and hydrophobic surfaces, which will facilitate uptake of intracellular and paracellular.Fig: The schematic diagram of Pc-AT-CLs administration and the transport process through the mucus layer and epithelial barrier.\u0000","PeriodicalId":501692,"journal":{"name":"The AAPS Journal","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142190469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Letter to the Editor on "Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies". 致编辑的信--"比较生物利用率研究中的分组治疗交互效应"。

The AAPS Journal Pub Date : 2024-09-09 DOI: 10.1208/s12248-024-00972-0

Wanjie Sun,Mohamed Alosh,Donald J Schuirmann,Stella Grosser

引用次数: 0

Prediction of Individual Disease Progression Including Parameter Uncertainty in Rare Neurodegenerative Diseases: The Example of Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS) 包括罕见神经退行性疾病参数不确定性在内的个体疾病进展预测：以常染色体易感性痉挛性共济失调（ARSACS）为例

The AAPS Journal Pub Date : 2024-04-30 DOI: 10.1208/s12248-024-00925-7

Niels Hendrickx, France Mentré, Andreas Traschütz, Cynthia Gagnon, Rebecca Schüle, Matthis Synofzik, Emmanuelle Comets

{"title":"Prediction of Individual Disease Progression Including Parameter Uncertainty in Rare Neurodegenerative Diseases: The Example of Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS)","authors":"Niels Hendrickx, France Mentré, Andreas Traschütz, Cynthia Gagnon, Rebecca Schüle, Matthis Synofzik, Emmanuelle Comets","doi":"10.1208/s12248-024-00925-7","DOIUrl":"https://doi.org/10.1208/s12248-024-00925-7","url":null,"abstract":"The aim of this study was to develop a model to predict individual subject disease trajectories including parameter uncertainty and accounting for missing data in rare neurological diseases, showcased by the ultra-rare disease Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). We modelled the change in SARA (Scale for Assessment and Rating of Ataxia) score versus Time Since Onset of symptoms using non-linear mixed effect models for a population of 173 patients with ARSACS included in the prospective real-world multicenter Autosomal Recessive Cerebellar Ataxia (ARCA) registry. We used the Multivariate Imputation Chained Equation (MICE) algorithm to impute missing covariates, and a covariate selection procedure with a pooled p-value to account for the multiply imputed data sets. We then investigated the impact of covariates and population parameter uncertainty on the prediction of the individual trajectories up to 5 years after their last visit. A four-parameter logistic function was selected. Men were estimated to have a 25% lower SARA score at disease onset and a moderately higher maximum SARA score, and time to progression (T50) was estimated to be 35% lower in patients with age of onset over 15 years. The population disease progression rate started slowly at 0.1 points per year peaking to a maximum of 0.8 points per year (at 36.8 years since onset of symptoms). The prediction intervals for SARA scores 5 years after the last visit were large (median 7.4 points, Q1-Q3: 6.4–8.5); their size was mostly driven by individual parameter uncertainty and individual disease progression rate at that time.<h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":501692,"journal":{"name":"The AAPS Journal","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability 用于量化批次间变异性的吸入丙酸氟替卡松和辛纳佛酸沙美特罗药代动力学模型

The AAPS Journal Pub Date : 2024-04-26 DOI: 10.1208/s12248-024-00913-x

Shuhui Li, Kairui Feng, Jieon Lee, Yuqing Gong, Fang Wu, Bryan Newman, Miyoung Yoon, Lanyan Fang, Liang Zhao, Jogarao V. S. Gobburu

{"title":"Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability","authors":"Shuhui Li, Kairui Feng, Jieon Lee, Yuqing Gong, Fang Wu, Bryan Newman, Miyoung Yoon, Lanyan Fang, Liang Zhao, Jogarao V. S. Gobburu","doi":"10.1208/s12248-024-00913-x","DOIUrl":"https://doi.org/10.1208/s12248-024-00913-x","url":null,"abstract":"Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100 μg FP/50 μg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1 µm, < 2 µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.","PeriodicalId":501692,"journal":{"name":"The AAPS Journal","volume":"161 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140799796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Implementation of a Three-Way Comparability Assessment for a Bioanalytical Anti-Drug Antibody Method 对生物分析抗药抗体方法实施三重可比性评估

The AAPS Journal Pub Date : 2024-04-18 DOI: 10.1208/s12248-024-00917-7

Rosanna S. Kwok, Ihsan Nijem, Ann Brady, Robert Hendricks

{"title":"Implementation of a Three-Way Comparability Assessment for a Bioanalytical Anti-Drug Antibody Method","authors":"Rosanna S. Kwok, Ihsan Nijem, Ann Brady, Robert Hendricks","doi":"10.1208/s12248-024-00917-7","DOIUrl":"https://doi.org/10.1208/s12248-024-00917-7","url":null,"abstract":"Immunogenicity evaluation is a critical part of drug development. Regulatory guidelines from multiple health agencies provide recommendations for the development and validation of anti-drug antibody (ADA) assays to assess immunogenicity in clinical trials. These recommendations primarily describe an ADA method run in one bioanalytical laboratory supporting a biotherapeutic molecule; however, there are increasing instances that may necessitate the support of the ADA method being run in more than one laboratory. A program can rapidly expand into multiple clinical studies within one or multiple countries, where the most appropriate way to support the program is by having multiple laboratories perform ADA sample analysis. In addition, there may be certain country-specific challenges that may make it infeasible to transport samples outside of the country for analysis. China for example has a lengthy sample exportation process that has potential to negatively impact study timelines. If multiple laboratories analyze samples using the same ADA method, comparable method performance should be established. Here, we describe a three-way assessment of ADA assay comparability between two US-based bioanalytical laboratories and one based in China.<h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":501692,"journal":{"name":"The AAPS Journal","volume":"87 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140628950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies 生物利用度比较研究中的组间相互作用效应

The AAPS Journal Pub Date : 2024-04-17 DOI: 10.1208/s12248-024-00921-x

Helmut Schütz, Divan A. Burger, Erik Cobo, David D. Dubins, Tibor Farkás, Detlew Labes, Benjamin Lang, Jordi Ocaña, Arne Ring, Anastasia Shitova, Volodymyr Stus, Michael Tomashevskiy

{"title":"Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies","authors":"Helmut Schütz, Divan A. Burger, Erik Cobo, David D. Dubins, Tibor Farkás, Detlew Labes, Benjamin Lang, Jordi Ocaña, Arne Ring, Anastasia Shitova, Volodymyr Stus, Michael Tomashevskiy","doi":"10.1208/s12248-024-00921-x","DOIUrl":"https://doi.org/10.1208/s12248-024-00921-x","url":null,"abstract":"Comparative bioavailability studies often involve multiple groups of subjects for a variety of reasons, such as clinical capacity limitations. This raises questions about the validity of pooling data from these groups in the statistical analysis and whether a group-by-treatment interaction should be evaluated. We investigated the presence or absence of group-by-treatment interactions through both simulation techniques and a meta-study of well-controlled trials. Our findings reveal that the test falsely detects an interaction when no true group-by-treatment interaction exists. Conversely, when a true group-by-treatment interaction does exist, it often goes undetected. In our meta-study, the detected group-by-treatment interactions were observed at approximately the level of the test and, thus, can be considered false positives. Testing for a group-by-treatment interaction is both misleading and uninformative. It often falsely identifies an interaction when none exists and fails to detect a real one. This occurs because the test is performed between subjects in crossover designs, and studies are powered to compare treatments within subjects. This work demonstrates a lack of utility for including a group-by-treatment interaction in the model when assessing single-site comparative bioavailability studies, and the clinical trial study structure is divided into groups.<h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\u0000","PeriodicalId":501692,"journal":{"name":"The AAPS Journal","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140616877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0