AAPS Journal最新文献_第9页

Correction: Assessing Immunogenicity in Drug Reviews and Prescribing Information in Japan. 更正：在日本评估药物审评和处方信息中的免疫原性。

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-12 DOI: 10.1208/s12248-025-01032-x

Mitsuru Ishibai, Megumi Kai, Hirokazu Wakuda, Ichiro Oikawa, Naoto Uemura

引用次数: 0

Pharmaceutical Sciences: Insights and Observations from Academic Chairs and Vice Chairs. 药物科学：学术主席和副主席的见解和观察。

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-04 DOI: 10.1208/s12248-025-01026-9

Kristy M Ainslie, Albert A Bowers, Robert H Chichewicz, Lara S Collier, Jonathan A Doorn, Christopher R Frei, Hamidreza Ghandehari, Robert B Gibbs, David S Lawrence, Craig R Lee, Donald E Mager, Paul Marker, Anna Schwendeman, Raj Suryanarayanan, Robert O Williams, Yaguang Xi, Wen Xie, Xiang-Qun Xie, Guizhi Zhu, Juliane Nguyen

{"title":"Pharmaceutical Sciences: Insights and Observations from Academic Chairs and Vice Chairs.","authors":"Kristy M Ainslie, Albert A Bowers, Robert H Chichewicz, Lara S Collier, Jonathan A Doorn, Christopher R Frei, Hamidreza Ghandehari, Robert B Gibbs, David S Lawrence, Craig R Lee, Donald E Mager, Paul Marker, Anna Schwendeman, Raj Suryanarayanan, Robert O Williams, Yaguang Xi, Wen Xie, Xiang-Qun Xie, Guizhi Zhu, Juliane Nguyen","doi":"10.1208/s12248-025-01026-9","DOIUrl":"10.1208/s12248-025-01026-9","url":null,"abstract":"On October 29, 2024, a virtual meeting, brought together chairs and vice chairs from several research-oriented U.S. Schools of Pharmacy to discuss the current landscape of pharmaceutical sciences, advocacy strategies, and best practices in graduate education. Key topics included alumni engagement, and the relatively low number of trainees interested in an academic career path. Dr. Dawn Beraud, the Executive Director of the American Institute for Medical and Biological Engineering (AIMBE) emphasized the importance of science advocacy, including increasing science funding and linking evidence-based decision making to policy. Discussions about graduate education highlighted best practices in using large language models, financial support challenges, and the significant role of industrial professionals in teaching. The proposed NextProf PharmSci program was discussed, which aims to address the imbalance of trainees leaning towards industry by preparing them for academic roles through a multi-day workshop. Participants expressed strong support for this initiative, emphasizing the need for a training pipeline and mentoring junior faculty. Participants agreed the event should be held annually, as it was found to be useful, and discussed future topics including sharing graduate and PharmD curricula as well as a shared summer school program.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"41"},"PeriodicalIF":5.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190382","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

Development of a PBPK Model for Lamotrigine which Incorporates Metabolism by UGT2B10: Impact of UGT2B10 Poor Metabolizer Phenotype and Pregnancy. 纳入UGT2B10代谢的拉莫三嗪PBPK模型的建立：UGT2B10代谢不良表型与妊娠的影响

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-04 DOI: 10.1208/s12248-025-01025-w

Iain Gardner, Aki T Heikkinen, Lloyd Wei Tat Tang, Kimberly Lapham, Theunis C Goosen

{"title":"Development of a PBPK Model for Lamotrigine which Incorporates Metabolism by UGT2B10: Impact of UGT2B10 Poor Metabolizer Phenotype and Pregnancy.","authors":"Iain Gardner, Aki T Heikkinen, Lloyd Wei Tat Tang, Kimberly Lapham, Theunis C Goosen","doi":"10.1208/s12248-025-01025-w","DOIUrl":"10.1208/s12248-025-01025-w","url":null,"abstract":"An updated physiologically based pharmacokinetic (PBPK) model was developed for lamotrigine by incorporating a component of metabolism due to a UDP-glucuronyltransferase (UGT) 2B isozyme. This was assigned to UGT2B10 based on recent in vitro data in our laboratory demonstrating metabolism of lamotrigine by this isozyme (Tang et al. AAPS J 26:107, 2024). The PBPK model developed in this work was able to reasonably recapitulate the exposure of lamotrigine after single (IV and Oral) and multiple (Oral) doses. The predicted/observed maximal plasma concentration (Cmax) ratio ranged from 0.8 to 1.4 across all simulated studies and for 16 out of 18 simulated studies was between 0.8 and 1.25. Similarly, the predicted/observed area under the curve (AUC) ratio ranged from 0.6 to 1.44 across all simulated studies and for 18 out of 26 of the simulated studies the ratio was between 0.8 and 1.25. There was a slight tendency to overpredict the lamotrigine AUC on multiple dosing. The median predicted fraction metabolised (fm) by UGT2B10 in the model was 60%. With this fm value, the in vivo clinical DDI between lamotrigine and valproate was reasonably recapitulated considering only UGT2B10 inhibition (Predicted/Observed AUC ratios ranged from 0.65 - 1.2). Information on the prevalence of UGT2B10 poor metabolizer phenotypes and longitudinal changes in UGT1A4 and UGT2B10 expression during pregnancy were incorporated into the PBPK model and the plasma concentrations in subjects with different UGT2B10 phenotypes and in different trimesters of pregnancy were simulated. The simulated concentrations in pregnant subjects were in line with those reported during pregnancy.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"40"},"PeriodicalIF":5.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191356","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

Prediction of Area Under the Curve from Urinary Vancomycin Concentrations Measured Using a Simple Method. 用简易方法预测尿万古霉素浓度曲线下面积。

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-04 DOI: 10.1208/s12248-025-01021-0

Yuki Oshima, Miyu Matsumoto, Sumika Munakata, Issei Tokimatsu, Norimichi Hattori, Toru Kotani, Sojiro Kusumoto, Hironori Sagara, Masaru Kato

{"title":"Prediction of Area Under the Curve from Urinary Vancomycin Concentrations Measured Using a Simple Method.","authors":"Yuki Oshima, Miyu Matsumoto, Sumika Munakata, Issei Tokimatsu, Norimichi Hattori, Toru Kotani, Sojiro Kusumoto, Hironori Sagara, Masaru Kato","doi":"10.1208/s12248-025-01021-0","DOIUrl":"10.1208/s12248-025-01021-0","url":null,"abstract":"Therapeutic drug monitoring (TDM) is recommended during vancomycin (VCM) administration to adjust the dosage such that the area under the curve (AUC) remains between 400 and 600 µg·h/mL (minimum inhibitory concentration = 1 µg/mL). However, measuring the AUC requires frequent blood sampling, which increases the burden of added time and cost for testing on both patients and healthcare personnel. Therefore, we aimed to address these issues by developing a simple and rapid method for measuring urinary VCM levels using solid-phase extraction and fluorescence spectrometry. The developed method had a quantification range of 100-2,000 µg/mL, with an accuracy of 100.0%-108.5% for concentrations of 200, 1,000, and 2,000 µg/mL. The intra- and inter-day relative standard deviations were below 3.39% and 4.48%, respectively. Furthermore, to predict the AUC from urinary VCM concentrations, we calculated the slope of the urinary concentrations at 7-12 h post-VCM administration in six patients. The slope for one patient differed significantly from that for the others, and the AUC was obtained using practical AUC-guided TDM for vancomycin (PAT) ver. 3.0c for the patient whose value deviated from the recommended range. A negative correlation was observed between the slope and AUC, with a correlation coefficient of 0.65, suggesting the potential for predicting AUC from urinary concentration trends. The use of urine samples, which can be easily obtained, for VCM dose adjustment is expected to contribute to providing more appropriate drug therapy to patients and reduce the burden on healthcare professionals.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"39"},"PeriodicalIF":5.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190459","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

Correction: Tumor-Targeted Chemoimmunotherapy with Immune-Checkpoint Blockade for Enhanced Anti-Melanoma Efficacy. 修正：肿瘤靶向化学免疫疗法与免疫检查点阻断增强抗黑色素瘤疗效。

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-03 DOI: 10.1208/s12248-025-01027-8

Man Li, Yuting Yang, Chaoqun Xu, Jiaojie Wei, Yingke Liu, Xingli Cun, Qianwen Yu, Xian Tang, Sheng Yin, Zhirong Zhang, Qin He

引用次数: 0

Impact of Dapagliflozin on Hepatic Lipid Metabolism and a Dynamic Model of Ketone Body Levels. 达格列净对肝脏脂质代谢的影响及酮体水平的动态模型。

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-03 DOI: 10.1208/s12248-025-01024-x

Zhijie Wan, Ming Yuan, Ziao Liu, Yuan Cai, Hua He, Kun Hao

{"title":"Impact of Dapagliflozin on Hepatic Lipid Metabolism and a Dynamic Model of Ketone Body Levels.","authors":"Zhijie Wan, Ming Yuan, Ziao Liu, Yuan Cai, Hua He, Kun Hao","doi":"10.1208/s12248-025-01024-x","DOIUrl":"10.1208/s12248-025-01024-x","url":null,"abstract":"The rising prevalence of metabolic-associated steatotic liver disease emphasizes the need to understand its lipid metabolism. Dapagliflozin may improve hepatic steatosis but could also increase the risk of ketoacidosis by elevating β-hydroxybutyrate (KB) levels. This study investigates dapagliflozin's effects on hepatic lipid metabolism and quantifies KB levels in vivo. Male Sprague-Dawley rats were fed either a normal diet or a high-fat diet (HFD) for 12 weeks. The HFD rats were then divided into four subgroups to receive vehicle, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg of dapagliflozin for four weeks. Free fatty acids (FFA) and KB levels were monitored, while protein and gene expression were analyzed. And a dynamic model of KB was developed for humans based on preclinical data. Dapagliflozin decreased body weight and visceral fat in HFD rats, increasing KB by upregulating CPT1a, HMGCS2, and HMGCL, and downregulating ACC. These changes correlated with reduced liver/fat index, liver pathology score, and oil-red staining area. A pharmacokinetic/pharmacodynamic (PK/PD) model was created from preclinical data to quantify KB levels in rats and validated in humans. Dapagliflozin reduces hepatic steatosis by enhancing fatty acid β-oxidation and ketogenesis and inhibiting fat synthesis. A dynamic model accurately predicts ketone body levels in treated individuals.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"38"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124061","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 Highly Sensitive Immunoassay to Enable Quantification of a Nanobody-Based Imaging Agent in Human Serum. 一种高度敏感的免疫分析方法，可以定量测定人血清中基于纳米体的显像剂。

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-03 DOI: 10.1208/s12248-025-01029-6

Sebastian Guelman, Catherine Huang, Kun Peng

{"title":"A Highly Sensitive Immunoassay to Enable Quantification of a Nanobody-Based Imaging Agent in Human Serum.","authors":"Sebastian Guelman, Catherine Huang, Kun Peng","doi":"10.1208/s12248-025-01029-6","DOIUrl":"10.1208/s12248-025-01029-6","url":null,"abstract":"Immuno-positron emission tomography (i-PET) is a non-invasive imaging technique that combines the specificity of monoclonal antibodies with the sensitivity of positron emission tomography to visualize and quantify the distribution of target antigens in vivo, providing detailed spatial information about the presence and localization of specific biomarkers. Due to the crucial role that cytotoxic T cells play in antitumor responses, a new tracer consisting of a humanized anti-CD8 nanobody labeled with fluorine-18 was developed to inform immuno-oncology treatments and support medical decision-making. Nanobodies are single-domain antibodies with low molecular weight and fast peripheral blood clearance, both of which are advantageous properties for same-day imaging. However, these unique characteristics pose bioanalytical challenges when developing clinical pharmacokinetic (PK) assays, including the need for high assay sensitivity. This manuscript focuses on overcoming bioanalytical challenges related to sensitivity and matrix interference during the development of a method to quantify this novel anti-CD8 nanobody tracer in human serum. Out of the three immunoassay platforms evaluated (ELISA, SMCxPRO™ and Gyrolab®), a Gyrolab method was ultimately selected due to its superior sensitivity, equal detectability of both conjugated and unconjugated forms of the nanobody and its ability to minimize matrix interference. By selecting the right assay format, along with the appropriate critical reagents for capture and detection, matrix interference was diminished. This novel PK method was successfully qualified demonstrating acceptable performance across all parameters. The acquired bioanalytical insights gained could be applied to nanobody-derived conjugates or other modalities that require high sensitivity in the clinical settings.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"37"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124057","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

Mechanistic Approach into 1,2,3-triazoles-based IIIM(S)-RS98 Mediated Apoptosis in Lung Cancer Cells. 1,2,3-三唑基IIIM(S)-RS98介导肺癌细胞凋亡的机制探讨

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-03 DOI: 10.1208/s12248-025-01018-9

Rigzin Dolkar, Gourav Paudwal, Davinder Singh, Chittaranjan Behera, Sumera Banoo Malik, Syed Mudassir Ali, Harjot Kaur, Amit Nargotra, Ravi Shankar, Shashank K Singh, Prem N Gupta

{"title":"Mechanistic Approach into 1,2,3-triazoles-based IIIM(S)-RS98 Mediated Apoptosis in Lung Cancer Cells.","authors":"Rigzin Dolkar, Gourav Paudwal, Davinder Singh, Chittaranjan Behera, Sumera Banoo Malik, Syed Mudassir Ali, Harjot Kaur, Amit Nargotra, Ravi Shankar, Shashank K Singh, Prem N Gupta","doi":"10.1208/s12248-025-01018-9","DOIUrl":"10.1208/s12248-025-01018-9","url":null,"abstract":"Lung cancer is a major public health problem across the globe, since it is the second most frequent cancer and the leading cause of cancer fatalities. This necessitates careful assessment of current therapies for lung cancer and discovery of novel drug candidates. 1,2,3 triazole compounds have emerged as an important class of prospective chemotherapeutic drugs for the treatment of lung cancer, with promising anti-lung cancer activity shown via a variety of pathways. They may interact with a various enzymes and receptors in cancer cells, causing cell cycle arrest and the activation of apoptosis. The present study aims to investigate the cytotoxic potential of institutional molecule based on 1,2,3 triazole [IIIM(S)-RS98] on multiple cancer cell lines. The compound was found to be most active on A549 cells and displayed the selectivity index as 8.16 in normal cells (e.g. HEK293). The in vitro findings revealed that IIIM(S)-RS98 induced apoptosis, loss of mitochondrial membrane potential, enhanced ROS and nitric oxide levels, and arrest cells in the G1 phase of the cell cycle. It inhibits the cell migration and clonogenic potential of A549 cells. Additionally, the downregulation of PI3K and p-Akt pathway leads to the activation of pro-apoptotic proteins Bax, downregulation of bcl2, activation of caspase 9, cleaved caspase 3, and cleaved parp1 expression and finally contribute towards apoptosis. Furthermore, molecular docking analysis indicated the interactions of IIIM(S)-RS98 with the apoptotic target proteins. The results demonstrated the potential of IIIM(S)-RS98 in the therapy of lung cancer.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"35"},"PeriodicalIF":5.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124063","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

Impact of Weak Vibration Generated by a Refrigerator on Protein Aggregation. 冰箱产生的弱振动对蛋白质聚集的影响

IF 5 3区医学

AAPS Journal Pub Date : 2025-01-27 DOI: 10.1208/s12248-025-01014-z

Shinji Kizuki, Zekun Wang, Satoru Yamauchi, Tetsuo Torisu, Susumu Uchiyama

{"title":"Impact of Weak Vibration Generated by a Refrigerator on Protein Aggregation.","authors":"Shinji Kizuki, Zekun Wang, Satoru Yamauchi, Tetsuo Torisu, Susumu Uchiyama","doi":"10.1208/s12248-025-01014-z","DOIUrl":"10.1208/s12248-025-01014-z","url":null,"abstract":"Protein aggregates and particles in biopharmaceuticals can induce adverse immune responses in patients. Thus, suppression of the formation of protein aggregates and particles is important for the successful development of therapeutic proteins. Mechanical stresses, including agitation, are widely recognized as stress factors that generate protein aggregates and particles. However, although refrigerators and storage chambers generate weak vibration, there have been no studies of the impact of such weak vibration on aggregate and particle formation during storage. In this study, monomer loss and aggregate formation of a CTLA4-Ig were evaluated during storage in a refrigerator (having a vibration acceleration less than 0.006 G) with or without three vibration isolators. The vibration isolators reduced the vibration acceleration, thereby decreasing the rate of monomer loss and nanometer-sized aggregate formation. The increase in the aggregation rate due to the weak vibration was not mitigated by adding poloxamer 188 or eliminating the air-liquid interface, which are processes known to be effective in preventing protein aggregation due to mechanical stresses. Thus, reducing vibration should be an effective way to mitigate the risk of aggregate formation.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"34"},"PeriodicalIF":5.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054129","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

Evaluating the Immunogenicity Risk of Protein Therapeutics by Augmenting T Cell Epitope Prediction with Clinical Factors. 用临床因素增强T细胞表位预测来评估蛋白质治疗药物的免疫原性风险。

IF 5 3区医学

AAPS Journal Pub Date : 2025-01-23 DOI: 10.1208/s12248-024-01003-8

Zicheng Hu, Patrick Wu, Steven J Swanson

{"title":"Evaluating the Immunogenicity Risk of Protein Therapeutics by Augmenting T Cell Epitope Prediction with Clinical Factors.","authors":"Zicheng Hu, Patrick Wu, Steven J Swanson","doi":"10.1208/s12248-024-01003-8","DOIUrl":"10.1208/s12248-024-01003-8","url":null,"abstract":"Protein-based therapeutics may elicit undesired immune responses in a subset of patients, leading to the production of anti-drug antibodies (ADA). In some cases, ADAs have been reported to affect the pharmacokinetics, efficacy and/or safety of the drug. Accurate prediction of the ADA response can help drug developers identify the immunogenicity risk of the drug candidates, thereby allowing them to make the necessary modifications to mitigate the immunogenicity. In this study, we leveraged the rich clinical study data collected by Roche/Genentech to identify factors that impact drug immunogenicity. We focused on conventional monoclonal antibodies, but have included a variety of additional drug modalities in the analysis. We show that the clinical ADA incidences are associated with the mechanism of action of the drugs, the mechanism of action of comedications, the routes of drug administration and the diseases of the patient cohort. By combining these clinical factors with the in silico epitope prediction, we improved the prediction accuracy of drug immunogenicity in clinical trials (AUC of cross validation improved from 0.72 to 0.93).","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"33"},"PeriodicalIF":5.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030224","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