AAPS Journal最新文献_第6页

Physiologically Based Modeling of Cefoxitin, Cefazolin, and Piperacillin Pharmacokinetics in Obese and Lean Rats. 肥胖和瘦肉大鼠头孢西丁、头孢唑林和哌拉西林药代动力学的生理建模。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-04-17 DOI: 10.1208/s12248-025-01063-4

Yi-Hua Sheng, Katarzyna Kosicka-Noworzyń, Anna Siemiątkowska, Sijia Yu, Raymond Rosa, Karan Sapra, Marian Awad, Justine Khalil, Thomas Doss, Christine Yohn, Luigi Brunetti, Leonid Kagan

{"title":"Physiologically Based Modeling of Cefoxitin, Cefazolin, and Piperacillin Pharmacokinetics in Obese and Lean Rats.","authors":"Yi-Hua Sheng, Katarzyna Kosicka-Noworzyń, Anna Siemiątkowska, Sijia Yu, Raymond Rosa, Karan Sapra, Marian Awad, Justine Khalil, Thomas Doss, Christine Yohn, Luigi Brunetti, Leonid Kagan","doi":"10.1208/s12248-025-01063-4","DOIUrl":"10.1208/s12248-025-01063-4","url":null,"abstract":"The prevalence of obesity is rapidly increasing worldwide, however there is a notable gap in understanding how obesity affects the pharmacokinetics of drugs and how dosing should be adjusted in obese population. The goals of this work were to evaluate plasma pharmacokinetics and tissue disposition of piperacillin, cefazolin, and cefoxitin in a rat model of diet-induced obesity compared to a lean cohort. Male Long-Evans rats were fed high-fat or control diets for 23 weeks. Various measures of body size and composition were collected. The animals were administered a mixture containing 50 mg/kg cefoxitin, 50 mg/kg cefazolin, and 120 mg/kg piperacillin. Plasma and tissues were collected and analyzed using a validated LC-MS/MS method. Whole-body physiologically-based pharmacokinetic (PBPK) models were develop to capture the biodistribution of these drugs in lean and obese cohorts. Most plasma and tissue concentrations were comparable between lean and obese rats after dosing based on mg/kg of total body weight; however, in some tissues concentration was consistently higher in obese animals. PBPKs successfully captured biodistribution of three drugs and both cohorts; however, cohort-specific (lean or obese) parameters were required for liver (for cefoxitin and cefazolin) and spleen (for all three drugs) for capturing the data.The results support the necessity of using mg/kg dosing for obese rats to achieve drug exposure comparable to that of lean rats. In the future, these models could be extended to predict plasma pharmacokinetics and tissue disposition of cefoxitin, cefazolin, and piperacillin in humans by incorporating interspecies scaling approaches.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"78"},"PeriodicalIF":3.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Assessing the Impact of Multiple Imputation Algorithms on Pharmacokinetic Model Performance: A Simulation-Based Study. 评估多种输入算法对药代动力学模型性能的影响：一项基于模拟的研究。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-17 DOI: 10.1208/s12248-025-01066-1

Thomas Duflot, Lucie Fayette, Céline Konecki, Jérémy Seurat, Catherine Feliu, Julien Scala-Bertola, Zoubir Djerada

{"title":"Assessing the Impact of Multiple Imputation Algorithms on Pharmacokinetic Model Performance: A Simulation-Based Study.","authors":"Thomas Duflot, Lucie Fayette, Céline Konecki, Jérémy Seurat, Catherine Feliu, Julien Scala-Bertola, Zoubir Djerada","doi":"10.1208/s12248-025-01066-1","DOIUrl":"10.1208/s12248-025-01066-1","url":null,"abstract":"This study compared multiple imputation (MI) algorithms in a one-compartment pharmacokinetic (PK) scenario with oral absorption. Four covariates (two continuous, two dichotomous) linked to PK parameters were randomly removed under a missing completely at random (MCAR) mechanism. The aim was to identify which algorithm best preserves covariate distributions and PK parameter estimates. The original dataset included 100 individuals, each with five sampling occasions. Missing data were introduced at 5%, 20%, 50%, and 75% for the four covariates under the MCAR assumption. Five MI algorithms (Mice, Amelia, missForest, rMIDAS, XGBoost) were tested. Absolute and relative errors and concordance metrics were used to assess performance. Population and individual parameter estimates were compared across imputed and original datasets using Monolix2024R1®. MissForest (MF) and Amelia yielded lower errors for continuous covariates whereas dichotomous variables were poorly imputed. Based on objective function values, Mice perform best at 5% and MF at 20% of missingness. Increasing missingness decreased covariate effects and increased the estimated inter-individual variances. Individual parameter estimation accurately captured individual-level variability across all imputed datasets. MI methods appear effective for covariate imputation in PK modeling, offering reliable results up to 20% missingness under an MCAR mechanism. Future research should explore refined strategies, including advanced modeling frameworks and Bayesian approaches for imputation. Enhancing our understanding of missing data processes will be crucial for robust PK analyses across diverse clinical settings.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"77"},"PeriodicalIF":5.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991068","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 Tool to Eliminate IgM Immunoassay Interference. 消除IgM免疫测定干扰的工具。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-11 DOI: 10.1208/s12248-025-01067-0

Alexander Pöhler, Uwe Wessels, Roland F Staack, Maria Nordgren, Rolf Lood, Kay-Gunnar Stubenrauch

引用次数: 0

Application of DOE to ELISA Robustness and Ruggedness Assessment. DOE在ELISA稳健性和耐用性评价中的应用。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-03 DOI: 10.1208/s12248-025-01048-3

Thy Follmer, Seth Clark, Thorsten Verch

{"title":"Application of DOE to ELISA Robustness and Ruggedness Assessment.","authors":"Thy Follmer, Seth Clark, Thorsten Verch","doi":"10.1208/s12248-025-01048-3","DOIUrl":"10.1208/s12248-025-01048-3","url":null,"abstract":"Complex assays such as immunoassays can be affected by robustness and ruggedness factors. Associated risks can be reduced by a systematic performance assessment across key factors followed by control strategies. However, the large number of factors and their interactions can represent an experimental challenge. Statistical Design of Experiments (DOE) allows efficient evaluation of more factors with fewer total assay runs in addition to assessing potential factor interactions. We applied DOEs to the robustness evaluation of a vaccine potency ELISA. Test factors were selected based on a review and ranking of development data, scientific experience, and commonly expected sources of variability. Comparing different design options with 16-20 runs which was a laboratory limit, a 16-run Resolution III design was selected based on the total number of runs, the degree of factor confounding, and the potential projection properties. DOE data were first visually analyzed by plotting the concentration-responses of reference curves against DOE Runs followed by detailed statistical models of the maximum fluorescent curve signal and the WRMSE fit values. Initial confounding between factors and their interactions was reduced by eliminating factors with no impact from the models and by removing factors or interactions based on their likelihood of an impact after applying statistical and scientific expertise. Despite initial confounding, the designs allowed discerning an impact of plate manufacturer with interaction of coating concentration and time out of 15 factors with only 16 runs.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"74"},"PeriodicalIF":5.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781656","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

Survey and Establishment of Points to Consider for Application of Analytical Techniques to Evaluate Protein Aggregates and Insoluble Particles in Biopharmaceuticals: Experiences in Japan Biopharmaceutical Consortium. 生物制药中蛋白质聚集体和不溶性颗粒分析技术应用的调查和考虑点的建立：日本生物制药协会的经验。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-03 DOI: 10.1208/s12248-025-01056-3

Hiroko Shibata, Satoshi Saitoh, Masato Kiyoshi, Yu Hayashi, Kazue Inaba, Shinji Katsura, Maho Sakurai, Yuka Komine, Shinji Okabe, Naomi Ohbayashi, Youko Kita, Hirokazu Kito, Masako Nakano, Kana Miyamoto, Akira Maruyama, Yuya Miyahara, Masanori Noda, Yasuyo Nozawa, Kazutaka Shimbo, Shota Kojima, Shinya Honda, Tetsuo Torisu, Susumu Uchiyama, Akiko Ishii-Watabe

{"title":"Survey and Establishment of Points to Consider for Application of Analytical Techniques to Evaluate Protein Aggregates and Insoluble Particles in Biopharmaceuticals: Experiences in Japan Biopharmaceutical Consortium.","authors":"Hiroko Shibata, Satoshi Saitoh, Masato Kiyoshi, Yu Hayashi, Kazue Inaba, Shinji Katsura, Maho Sakurai, Yuka Komine, Shinji Okabe, Naomi Ohbayashi, Youko Kita, Hirokazu Kito, Masako Nakano, Kana Miyamoto, Akira Maruyama, Yuya Miyahara, Masanori Noda, Yasuyo Nozawa, Kazutaka Shimbo, Shota Kojima, Shinya Honda, Tetsuo Torisu, Susumu Uchiyama, Akiko Ishii-Watabe","doi":"10.1208/s12248-025-01056-3","DOIUrl":"10.1208/s12248-025-01056-3","url":null,"abstract":"Protein aggregates and insoluble particles in biopharmaceutical products are impurities that can elicit immunogenicity. The protein aggregates and insoluble particles form during manufacturing and storage, and should be characterized to optimize the manufacturing process and establish a control strategy. Several issues regarding the evaluation and control of these particles have been concerned, and collaborative studies have been conducted in the Japan Biopharmaceutical Consortium to address them. However, there is still no consensus for utilizing analytical techniques in parallel to establish a control strategy for such protein aggregates and insoluble particles, which range in size from a few nanometers to several hundred micrometers. Therefore, in this study, we surveyed Japanese biopharmaceutical companies through a questionnaire including questions regarding analytical techniques used to establish control strategies for protein aggregates and insoluble particles at various development phases. To summary the survey results, we found that size exclusion chromatography, light obscuration, and visual inspection are consistently used from early development and formulation optimization stage to commercial manufacturing. Apart from the light obscuration method, flow imaging (FI) was the most commonly used technique for subvisible particle characterization; thus, the use of FI to establish a control strategy was documented. The recommendation for establishing a control strategy for protein aggregates and insoluble particles based on life-cycle of drug development are summarized.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"75"},"PeriodicalIF":5.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781888","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

GCN-BBB: Deep Learning Blood-Brain Barrier (BBB) Permeability PharmacoAnalytics with Graph Convolutional Neural (GCN) Network. GCN-BBB：基于图卷积神经网络的深度学习血脑屏障（BBB）渗透性药物分析。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-03 DOI: 10.1208/s12248-025-01059-0

Yankang Jing, Guangyi Zhao, Yuanyuan Xu, Terence McGuire, Ganqian Hou, Jack Zhao, Maozi Chen, Oscar Lopez, Ying Xue, Xiang-Qun Xie

{"title":"GCN-BBB: Deep Learning Blood-Brain Barrier (BBB) Permeability PharmacoAnalytics with Graph Convolutional Neural (GCN) Network.","authors":"Yankang Jing, Guangyi Zhao, Yuanyuan Xu, Terence McGuire, Ganqian Hou, Jack Zhao, Maozi Chen, Oscar Lopez, Ying Xue, Xiang-Qun Xie","doi":"10.1208/s12248-025-01059-0","DOIUrl":"10.1208/s12248-025-01059-0","url":null,"abstract":"The Blood-Brain Barrier (BBB) is a selective barrier between the Central Nervous System (CNS) and the peripheral system, regulating the distribution of molecules. BBB permeability has been crucial in CNS-targeting drug development, such as glioblastoma-related drug discovery. In addition, more CNS diseases still present significant challenges, for instance, neurological disorders like Alzheimer's Disease (AD) and drug abuse. Conversely, cannabinoid drugs that do not cross the BBB are needed to avoid off-target CNS psychotropic effects. In vitro and in vivo experiments measuring BBB permeability are costly and low throughput. Computational pharmacoanalytics modeling, particularly using deep-learning Graph Neural Networks (GNNs), offers a promising alternative. GNNs excel at capturing intricate relationships in graph-based information, such as small molecular structures. In this study, we developed GNNs model for BBB permeability using the graph representation of drugs. The GNNs were compared with other algorithms using molecular fingerprints or physical-chemical descriptors. With a dataset of 1924 molecules, the best GNNs model, a convolutional graph neural network using a normalized Laplacian matrix (GCN_2), achieved a precision of 0.94, recall of 0.96, F1 score of 0.95, and MCC score of 0.77. This outperformed other machine learning algorithms with molecular fingerprints. The findings indicate that the graphic representation of small molecules combined with GNNs architecture is powerful in predicting BBB permeability with high accuracy and recall. The developed GNNs model can be utilized in the initial screening stage for new drug development.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"73"},"PeriodicalIF":5.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781886","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

Virtual Bioequivalence Assessment of Tofacitinib Once Daily Modified Release Dosage Form in Pediatric Subjects. 托法替尼每日一次修正释放剂型在儿科受试者中的虚拟生物等效性评估

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-01 DOI: 10.1208/s12248-025-01057-2

Kazuko Sagawa, Vivek Purohit, Vu Le, Hao-Jui Hsu, Martin E Dowty, Susanna Tse, Cheng Chang

{"title":"Virtual Bioequivalence Assessment of Tofacitinib Once Daily Modified Release Dosage Form in Pediatric Subjects.","authors":"Kazuko Sagawa, Vivek Purohit, Vu Le, Hao-Jui Hsu, Martin E Dowty, Susanna Tse, Cheng Chang","doi":"10.1208/s12248-025-01057-2","DOIUrl":"10.1208/s12248-025-01057-2","url":null,"abstract":"Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate release (IR) tablets, modified release (MR) tablets and IR solution. A once daily MR microsphere formulation was developed for pediatric patients. Previously, bioequivalence (BE) between the 10 mg once daily (QD) MR microsphere formulation and 5 mg twice daily (BID) IR solution has been established with PBPK virtual BE trials (VBE) in place of a clinical BE trial in healthy adult population. In this research, the PBPK model based VBE approach was extended to pediatric population. Pediatric PBPK model verification was conducted by first examining predicted vs observed demographic information such as body weight (BWT) and glomerular filtration rate (GFR). After confirming the alignment in demographic background between clinical study participants vs virtual pediatric subjects, multiple ontogeny profiles for CYP3A4 and CYP2C19 were examined. The established model predicted AUC and Cmax within 1.5-fold of observed values for multiple trials, age groups and formulations. Lastly, VBE trials in pediatric subjects were conducted with PBPK model generated pharmacokinetic (PK) parameter values with clinically observed intra-subject coefficient of variation (ICV) in adults. Since ICV in pediatric population is unknown, the sensitivity around ICV was also evaluated to assess the BE risk between IR solution and MR microsphere formulation in pediatric population. The results demonstrated that the IR oral solution BID and MR microsphere formulation QD are BE in pediatric population.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"71"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765814","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 FcRn Binding on Monoclonal Antibody Disposition in the Brain. FcRn 结合对脑部单克隆抗体处置的影响

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-01 DOI: 10.1208/s12248-025-01060-7

Hsien Wei Huang, Shengjia Wu, Shufang Liu, Dhaval K Shah

{"title":"Effect of FcRn Binding on Monoclonal Antibody Disposition in the Brain.","authors":"Hsien Wei Huang, Shengjia Wu, Shufang Liu, Dhaval K Shah","doi":"10.1208/s12248-025-01060-7","DOIUrl":"10.1208/s12248-025-01060-7","url":null,"abstract":"This study investigates the role of FcRn in brain disposition of monoclonal antibodies. Human FcRn (hFcRn) expressing mice and different FcRn binding variants of a non-target binding antibody trastuzumab (WT) were used for the investigation. The FcRn binding mutations were: YTE, YPY, YQAY, and IHH. YQAY and YPY mutants have enhanced FcRn binding at both neutral and acidic pH (7+/6+). YTE mutant has enhanced FcRn binding at only acidic pH (7-/6+), and IHH mutant has no FcRn binding (7-/6-). The pharmacokinetics (PK) of these mutants in plasma, brain interstitial fluid (ISF), and brain homogenate were measured following intravenous administration. The area under the concentration-time curve (AUC) for all PK profiles and ratios of brain and plasma AUCs were calculated for comparison. Results showed that WT antibody had brain:plasma AUC ratio of 0.70% and ISF:plasma AUC ratio of 0.59%. Among all mutants, YPY exhibited the highest AUC ratio for brain (3.86%) and ISF (3.49%). YQAY had relatively high AUC ratios of 1.49% in the brain and 0.81% in ISF. YTE showed a similar AUC ratio in the brain (0.60%) and ISF (0.62%) compared to WT, while IHH exhibited similar AUC ratio in the brain (0.52%) but higher AUC ratio in ISF (2.48%). The results suggest that binding to FcRn at neutral and acidic pH facilitates transcytosis of antibody into the brain. Just increasing the binding to FcRn at acidic pH does not impact the disposition of antibody in the brain. Complete removal of FcRn binding might lead to prolonged retention of antibody in ISF. Together, these data demonstrate that FcRn significantly affects brain disposition of antibody, and engineering of Fc domain to alter the binding of antibody to FcRn may be exploited to achieve better exposure of antibodies in the brain.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"72"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765810","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

Leveraging Buprenorphine and Halofantrine as Tool Molecules to Develop a Novel Semi-Physiologically based Pharmacokinetic Model Accounting for Gastro-Intestinal Lymphatic Absorption and Enabling Cross-Species Translation. 利用丁丙诺啡和卤啡碱作为工具分子，开发一种新的半生理的药代动力学模型，用于胃肠道淋巴吸收和跨物种翻译。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-26 DOI: 10.1208/s12248-025-01053-6

Xun Tao, Shraddha Sadekar, Douglas Leipold, Gregory Z Ferl, Eric Gary Stefanich, Amrita V Kamath

{"title":"Leveraging Buprenorphine and Halofantrine as Tool Molecules to Develop a Novel Semi-Physiologically based Pharmacokinetic Model Accounting for Gastro-Intestinal Lymphatic Absorption and Enabling Cross-Species Translation.","authors":"Xun Tao, Shraddha Sadekar, Douglas Leipold, Gregory Z Ferl, Eric Gary Stefanich, Amrita V Kamath","doi":"10.1208/s12248-025-01053-6","DOIUrl":"10.1208/s12248-025-01053-6","url":null,"abstract":"Intestinal lymphatic absorption is a crucial alternative to portal uptake for highly lipophilic drugs (log P > 5), bypassing first-pass metabolism. Unlike the portal-hepatic pathway, lymphatic uptake is rarely considered in physiologically based pharmacokinetic (PBPK) models for oral delivery. Our study developed an innovative Gastro-Intestinal (GI)-lymph-PBPK model that includes GI absorption, chylomicron extraction (CE) to rescue drugs from gut extraction (GE), and bypass hepatic extraction (HE). This model introduces CE clearance (CLCE), competing with GE clearance, to estimate the drug proportion subjected to CE versus GE. PBPK analysis for Buprenorphine revealed extensive GE (0.87) and HE (0.58), explaining the low bioavailability (F%) of 5.28% in rats. Buprenorphine prodrugs activated CLCE, leading to CE ranging from 0.37 to 0.79, boosting oral F% to 39.9%-79.9% in rats. To translate from rat to human, our model considered species differences in GI transit time, formulation, food-dependent drug dissolution, allometric scaling in CLCE, and between species variability in gut metabolism. Using Halofantrine, we established an allometric scaling factor for CLCE at 1.1. Accounting for six times faster human gut metabolism, our model predicted an extremely low oral F% of 0.382% for Buprenorphine in humans. Incorporating the allometric scaled CLCE competing with the extensive gut metabolism, our model predicted Buprenorphine prodrugs remains effective in enabling substantial absorption boosts, with oral F% estimates ranging from 15.8% to 56.7% in humans. This study highlights the significant potential of GI-lymph-PBPK modeling in predicting intestinal lymphatic absorption and facilitating cross-species translation.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"67"},"PeriodicalIF":5.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722583","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 a Platform Method for Physical Appearance Assessment of New Parenteral Pharmaceuticals. 新型注射用药物外观评价平台方法的建立。

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-26 DOI: 10.1208/s12248-025-01049-2

Ying Wan, Walter Wasylaschuk, Joseph Straub, Wei Xu, Nicole Lepo, Patricia M Egan, Jillian Acevedo-Skrip, Elizabeth Thoryk, Megan Mackey

{"title":"Establishing a Platform Method for Physical Appearance Assessment of New Parenteral Pharmaceuticals.","authors":"Ying Wan, Walter Wasylaschuk, Joseph Straub, Wei Xu, Nicole Lepo, Patricia M Egan, Jillian Acevedo-Skrip, Elizabeth Thoryk, Megan Mackey","doi":"10.1208/s12248-025-01049-2","DOIUrl":"10.1208/s12248-025-01049-2","url":null,"abstract":"Physical appearance (PA) is an attribute indicating the quality of parenteral pharmaceuticals. It is routinely evaluated during release and stability testing and included in regulatory filings. PA assessment of liquids involves three tests: visible particulates, clarity, and color. For each test, compendial general method chapters are available requiring minimal modification. This allows for a platform PA method approach, streamlining method readiness for new test articles. However, selecting the appropriate method is challenging, as no method suits all test articles, and pharmacopeias do not specify suitable condition(s) for each method. Improper method selection can lead to inappropriate specification setting and unreliable results. The need for guidance is especially urgent for vaccines, which often exhibit a wide range of PA attributes due to complex delivery systems and adjuvants that boost immunogenicity. This manuscript addresses this challenge by explaining method suitability and presenting a decision table for PA method selection based on the appearance properties of pharmaceuticals. A case study involving a yellow-turbid vaccine adjuvant is presented to demonstrate the practical application of the decision table. When color and turbidity make visual comparison to reference liquids difficult, instrumental clarity and visual qualitative methods are suitable options. The manuscript provides valuable insights on PA method selection and setting specifications for new parenteral pharmaceuticals. Furthermore, the decision table enables platform methods for test articles sharing similar appearance properties, eliminating the need for individual methods, reducing document preparation time for method and verification protocol, and enhancing the consistency and efficiency of GMP testing for PA.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"69"},"PeriodicalIF":5.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722582","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