AAPS Journal最新文献

Stability of Anti-Drug Antibodies Against Antibody Therapeutics.

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-15 DOI: 10.1208/s12248-025-01030-z

Parul Sirohi, Kelly Hainline, Heather Bullock, Sihe Wang, Robert J Konrad, Yi Wen

引用次数: 0

Analysis on the Impact of U.S. FDA's Narrow Therapeutic Index Bioequivalence Criteria on Generic Drug Applications.

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-12 DOI: 10.1208/s12248-025-01020-1

Krista Anim Anno, Mirette Mina, Zhen Zhang, Lei Zhang, Wenlei Jiang

{"title":"Analysis on the Impact of U.S. FDA's Narrow Therapeutic Index Bioequivalence Criteria on Generic Drug Applications.","authors":"Krista Anim Anno, Mirette Mina, Zhen Zhang, Lei Zhang, Wenlei Jiang","doi":"10.1208/s12248-025-01020-1","DOIUrl":"https://doi.org/10.1208/s12248-025-01020-1","url":null,"abstract":"Since 2012, the U.S. Food and Drug Administration (FDA) has developed classification criteria of narrow therapeutic index (NTI) drug products and tightened bioequivalence (BE) standards for these products by recommending a fully replicated, two-sequence, two-treatment, four-period crossover study design where BE is based on passing both scaled average BE criterion and within-subject variability comparison criterion, as well as the average BE criterion of 80.00%-125.00%. Currently, the BE study design and criteria for NTI drugs are somewhat different across regulatory agencies. The objective of this study is to survey pharmacokinetic BE data of abbreviated new drug applications (ANDAs) of NTI drugs submitted to the FDA with initial submission dates between January 1, 2013 and October 1, 2022 to identify the impact of FDA's current BE approach on generic NTI approval. Thirty-three NTI drug products from 100 ANDAs were identified with 93 ANDAs included in analysis. Eighty-seven ANDAs had four-way crossover studies, with 69 and 106 fed and fasting BE studies, respectively. For all NTI drugs, the range of average SWR for Cmax, AUCt, and AUCinf was between 0.05 and 0.27. Of the 20 studies that failed BE, 90%, 5%, and 5% failed reference scaled criteria only, variability comparison criteria only, and both, respectively. Further communication of this work with global regulatory agencies and the scientific community will help better understand current FDA NTI BE criteria and review experiences. These efforts will support the development of harmonized BE criteria for NTI drugs, in turn improving patient access to generic NTI drugs.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"42"},"PeriodicalIF":5.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411457","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

Application of a Physiologically Based Pharmacokinetic Approach to Predict Tenofovir Pharmacokinetics During Pregnancy.

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-12 DOI: 10.1208/s12248-025-01031-y

Khaled Abduljalil, Mailys De Sousa Mendes, Farzaneh Salem, Sihem Benaboud, Iain Gardner

{"title":"Application of a Physiologically Based Pharmacokinetic Approach to Predict Tenofovir Pharmacokinetics During Pregnancy.","authors":"Khaled Abduljalil, Mailys De Sousa Mendes, Farzaneh Salem, Sihem Benaboud, Iain Gardner","doi":"10.1208/s12248-025-01031-y","DOIUrl":"https://doi.org/10.1208/s12248-025-01031-y","url":null,"abstract":"Pharmacotherapy during pregnancy requires a better understanding of the impact of changes in maternal physiology on the maternal and fetal drug exposure. The physiologically based pharmacokinetic (PBPK) modelling approach can be applied to predict maternal and fetal exposure. In vitro and in vivo PK data in non-pregnant individuals were compiled and used to develop and verify a PBPK model for tenofovir. The model was then used to predict the maternal and fetal tenofovir exposure during pregnancy, after incorporation of current knowledge on maternal and fetal physiological changes during pregnancy. Predicted concentrations and parameters from the PBPK model were compared to observed data. Predicted tenofovir PK agreed with observations in non-pregnant (13 studies) and pregnant (7 studies with differing gestational weeks) individuals. Observed concentrations fell within the PBPK 5th - 95th prediction intervals. Predicted PK parameters were within twofold of the reported parameters. The predicted tenofovir steady state cord-to-maternal exposure ratio at term was 0.85 (range: 0.62-0.98), which agrees with clinically observed ratios ranging between 0.60-1.00. A PBPK model for tenofovir was constructed and used to simulate the maternal and fetal exposure to tenofovir in virtual pregnant women population at different gestational weeks. Applying a similar approach to other drugs or chemicals may allow exposure prediction and risk assessment in the fetus following maternal administration of drugs or unintended exposure to environmental toxicants.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"43"},"PeriodicalIF":5.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411459","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: Assessing Immunogenicity in Drug Reviews and Prescribing Information in Japan.

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.

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

Prediction of Area Under the Curve from Urinary Vancomycin Concentrations Measured Using a Simple Method.

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":"https://doi.org/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

Development of a PBPK Model for Lamotrigine which Incorporates Metabolism by UGT2B10: Impact of UGT2B10 Poor Metabolizer Phenotype and Pregnancy.

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":"https://doi.org/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

A Highly Sensitive Immunoassay to Enable Quantification of a Nanobody-Based Imaging Agent in Human Serum.

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":"https://doi.org/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

Correction: Tumor-Targeted Chemoimmunotherapy with Immune-Checkpoint Blockade for Enhanced Anti-Melanoma Efficacy.

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.

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":"https://doi.org/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