AAPS Journal最新文献

Predictive Performance of pyDarwin-Selected Versus Expert-Developed Paediatric Tobramycin Population Pharmacokinetic Models for Model-Informed Precision Dosing. 达尔文选择的与专家开发的儿科妥布霉素群体药代动力学模型的预测性能模型知情的精确剂量。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-10-19 DOI: 10.1208/s12248-026-01321-z

Jinglei Wang, Kiera Harwood, Wenyu Yang, Alice Lei, Tony Lai, Keith Nieforth, Stephen Duffull, Mark Sale, Amanda Gwee, Xiao Zhu

{"title":"Predictive Performance of pyDarwin-Selected Versus Expert-Developed Paediatric Tobramycin Population Pharmacokinetic Models for Model-Informed Precision Dosing.","authors":"Jinglei Wang, Kiera Harwood, Wenyu Yang, Alice Lei, Tony Lai, Keith Nieforth, Stephen Duffull, Mark Sale, Amanda Gwee, Xiao Zhu","doi":"10.1208/s12248-026-01321-z","DOIUrl":"https://doi.org/10.1208/s12248-026-01321-z","url":null,"abstract":"PyDarwin is an open-source Python package integrating machine learning with NONMEM for automated model selection; however, its utility in model-informed precision dosing (MIPD) remains unvalidated. This study aims to evaluate pyDarwin for population pharmacokinetics (PopPK) model development in MIPD compared with expert-developed models, using paediatric tobramycin as a representative case. The model-building dataset included 450 plasma concentrations from 63 children with cystic fibrosis (CF). One group manually developed a model using stepwise covariate selection, while another applied pyDarwin within a predefined 27-dimensional model space, using a fitness function that incorporated a penalty based on 24-h area under the curve (AUC24h). External validation was performed using 1011 concentrations from 144 children, including evaluation using all therapeutic drug monitoring (TDM) data and clinically relevant MIPD scenarios (a priori [AP], Bayesian 1, Bayesian 2). Both models included weight-based scaling, a maturation function, and estimated glomerular filtration rate as covariates on clearance, yielding comparable clearance estimates. The pyDarwin-selected model was a two-compartment model with fixed allometric scaling exponents, whereas the manual model was a one-compartment model with estimated exponents. Both models showed comparable probability of target attainment for steady-state AUC24h. In external validation using all TDM data, the pyDarwin-selected model demonstrated better predictive performance for CF patients than manual model (prediction-based MPE -14.6% vs -41.6%; MAPE 34.0% vs 54.4%). In MIPD scenarios, the pyDarwin-selected model showed superior performance in the AP setting, with differences diminishing after Bayesian updating. These findings support pyDarwin-based automated PopPK model selection as a reliable and efficient framework for MIPD.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225390","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

The Patient-Centric Formulation Compass: A Proposed Bottom-Up Framework to Translate Population Insights into Product Design. 以患者为中心的配方指南针：将人口洞察转化为产品设计的自下而上框架。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-10-15 DOI: 10.1208/s12248-026-01322-y

Domagoj Segregur, Pascal Somville, Jérôme Mantanus, Talia Flanagan

{"title":"The Patient-Centric Formulation Compass: A Proposed Bottom-Up Framework to Translate Population Insights into Product Design.","authors":"Domagoj Segregur, Pascal Somville, Jérôme Mantanus, Talia Flanagan","doi":"10.1208/s12248-026-01322-y","DOIUrl":"10.1208/s12248-026-01322-y","url":null,"abstract":"Patient-centricity is increasingly recognized as an important objective in pharmaceutical development. However, despite growing emphasis on incorporating patient perspectives into medicine design, limited guidance exists on how patient-centric insights can be systematically translated into administration route and formulation selection during early development. This white paper discusses the challenge associated with integrating patient-centric considerations into formulation-related decision-making and presents the authors' perspective on how these challenges may be addressed through a structured framework. To support this objective, the Patient-Centric Formulation Compass (PCFC) is proposed as a framework that links patient and disease understanding with administration route selection, formulation assessment, developability considerations, and downstream development planning. The framework consists of four sequential stages: 1) assessment of the target population and disease, 2) identification of suitable administration routes and formulation options, 3) evaluation of drug candidate compatibility and optimization opportunities, and 4) consolidation of the resulting knowledge into a transparent development summary. Rather than introducing new patient-centric principles, PCFC aims to operationalize and connect existing concepts within a structured and repeatable decision-support approach that may facilitate multidisciplinary discussion and formulation strategy development. The framework is proposed as a reference model that organizations may adapt to their own context and expertise. Its utility and impact should be evaluated through broader application across diverse development programs and therapeutic areas.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197608","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

Physiologically based Biopharmaceutics Modeling (PBBM) Reveals a Low Dissolution-related Bioequivalence Risk for Immediate-Release Amlodipine Tablets. 基于生理的生物制药模型（PBBM）揭示了速释氨氯地平片低溶出度相关生物等效性风险。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-10-12 DOI: 10.1208/s12248-026-01319-7

Porfirio de la Cruz Cruz, Larissa Lopes Rodrigues Gomide, Gabriela Moraes do Nascimento, José Trinidad Pérez Urizar, Alberto Martínez Muñoz, Ángel Antonio Vértiz Hernández, Amaury de Jesús Pozos Guillén, Héctor Eduardo Flores Reyes, Ricardo Zamora Ramírez, Luis Manuel Romero Cruz, Marcelino García Sánchez, Mauricio A García, Michele Georges Issa, Marcelo Dutra Duque

{"title":"Physiologically based Biopharmaceutics Modeling (PBBM) Reveals a Low Dissolution-related Bioequivalence Risk for Immediate-Release Amlodipine Tablets.","authors":"Porfirio de la Cruz Cruz, Larissa Lopes Rodrigues Gomide, Gabriela Moraes do Nascimento, José Trinidad Pérez Urizar, Alberto Martínez Muñoz, Ángel Antonio Vértiz Hernández, Amaury de Jesús Pozos Guillén, Héctor Eduardo Flores Reyes, Ricardo Zamora Ramírez, Luis Manuel Romero Cruz, Marcelino García Sánchez, Mauricio A García, Michele Georges Issa, Marcelo Dutra Duque","doi":"10.1208/s12248-026-01319-7","DOIUrl":"10.1208/s12248-026-01319-7","url":null,"abstract":"A conservative BCS class III classification was recently proposed for amlodipine based on inconclusive permeability evidence. However, the scarce in vivo data suggest that amlodipine is slowly, though completely, absorbed. This means that the very rapid dissolution criterion associated with a BCS class III classification may be overly restrictive for immediate-release amlodipine products. The aim of this manuscript was to develop and validate a physiologically based biopharmaceutics model (PBBM) to assess the risk of bioequivalence failure associated with dissolution. Given that amlodipine is a lipophilic weak base, the absorption model incorporated a surrogate representation of intracellular lysosomal trapping through the FuEnt parameter, resulting in an adequate description of oral pharmacokinetics. Dissolution input included in vitro profiles obtained in phosphate buffer pH 6.8 at 50 rpm for different multisource products, fitted to either the Johnson model or the Z-factor approach. Although several products did not meet biowaiver dissolution criteria, virtual bioequivalence simulations conducted with the validated PBBM consistently predicted bioequivalence across tested formulations. Overall, these findings suggest that dissolution differences would have limited impact on the in vivo performance of amlodipine and support a low dissolution-related bioequivalence risk for immediate-release amlodipine tablets.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170756","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

Liquid Chromatography/tandem Mass Spectrometry-based Target Engagement of Lysine-specific Demethylase 1 Inhibitor TAK-418 Through Detecting Covalent Adducts in the Brain. 基于液相色谱/串联质谱的赖氨酸特异性去甲基酶1抑制剂TAK-418通过检测大脑共价加合物的靶向作用

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-10-12 DOI: 10.1208/s12248-026-01320-0

Kota Matsumiya, Shinji Iwasaki, Satoru Matsuda, Yohei Kosugi, Hisao Shimizu, Masaaki Kakehi, Rina Baba, Nobuyuki Amano, Atsushi Nakatani, Haruhide Kimura, Hideki Hirabayashi

{"title":"Liquid Chromatography/tandem Mass Spectrometry-based Target Engagement of Lysine-specific Demethylase 1 Inhibitor TAK-418 Through Detecting Covalent Adducts in the Brain.","authors":"Kota Matsumiya, Shinji Iwasaki, Satoru Matsuda, Yohei Kosugi, Hisao Shimizu, Masaaki Kakehi, Rina Baba, Nobuyuki Amano, Atsushi Nakatani, Haruhide Kimura, Hideki Hirabayashi","doi":"10.1208/s12248-026-01320-0","DOIUrl":"10.1208/s12248-026-01320-0","url":null,"abstract":"Translating pharmacokinetics (PK) and pharmacodynamics (PD) from preclinical to clinical is important in successful development of drugs for central nervous system (CNS) diseases. TAK-418 is a clinical candidate of lysine-specific demethylase 1 (LSD1) inhibitor with a unique mechanism of action; it covalently binds to flavin adenine dinucleotide (FAD) to form a compact adduct formylated FAD (F-FAD), thereby minimizing hematological side effect risks. In this study, we established a liquid chromatography-tandem mass spectrometry (LC/MS/MS)-based approach for evaluating F-FAD as a target engagement marker for TAK-418 to advance PK/PD translation and clinical dose setting. In rats, LC/MS/MS enabled detection of TAK-418-induced F-FAD formation in the brain with chromatographic separation from native FAD. F-FAD levels were positively associated with LSD1 protein abundance across brain regions and increased with increasing TAK-418 dose. LSD1 occupancy calculated from F-FAD concentrations was correlated with the inhibition level of LSD1 enzyme activity in rat hippocampus. This mechanism-based approach provides a link between covalent adduct formation, target engagement, and enzyme inhibition in the brain. In addition, similar point estimates of the half-maximal effective concentration (EC50) for F-FAD formation in rat and human hippocampal homogenates support the potential utility of F-FAD measurements for translational assessment of LSD1 target engagement. These findings provide useful information for evaluating the translational relationship between TAK-418 exposure and LSD1 target engagement and may support future PK/PD modeling and clinical dose selection for TAK-418. Moreover, our methodology for measuring covalent adducts would be applicable for multiple CNS drug candidates with covalent binding property.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171954","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

Insights into Drug Absorption Impairment Mechanisms in Hepatic Impairment using Physiologically-based Pharmacokinetic Modelling: A Case Study with Nilotinib. 利用基于生理的药代动力学模型研究肝损害的药物吸收损伤机制：以尼洛替尼为例。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-10-07 DOI: 10.1208/s12248-026-01317-9

Laura G Al-Amiry Santos, Chara Litou, Karen Rowland Yeo

{"title":"Insights into Drug Absorption Impairment Mechanisms in Hepatic Impairment using Physiologically-based Pharmacokinetic Modelling: A Case Study with Nilotinib.","authors":"Laura G Al-Amiry Santos, Chara Litou, Karen Rowland Yeo","doi":"10.1208/s12248-026-01317-9","DOIUrl":"10.1208/s12248-026-01317-9","url":null,"abstract":"Nilotinib is reported to have a reduced maximal drug concentration (Cmax) in patients with hepatic impairment (HI). Given this compound is poorly soluble, highly lipophilic and has a positive food effect, reduced absorption in HI may be due to impaired micelle-mediated solubility resulting from reduced intestinal bile salts. PBPK modelling can be used to test this hypothesis as well as being a diagnostic tool to elucidate other potential mechanisms not captured by the base model. In this study, a mechanistic PBPK model for nilotinib was developed and its performance was evaluated in HI patients. A 'learn-and-confirm' approach was taken, using clinical food effect data to validate the model's mechanistic sensitivity to bile salt-mediated solubility. The final model recovered clinical studies well, with area-under-the-curve (AUC) and Cmax being within 0.8 - 1.25-fold for fasted studies and 1.5-fold for fed/fasted ratios. AUC and Cmax were well recovered in mild HI (within 0.8 - 1.25-fold) and reasonably well recovered in moderate HI (within twofold) but significantly overpredicted in severe HI (> twofold). Bile salt concentrations were reduced across gastrointestinal segments for moderate and severe HI in line with in vitro data. Following twofold and 2.5-fold reductions in bile salts in moderate and severe HI, respectively, sensitivity was minor. Given uncertainty around the fugut, this was reduced to better recover the Cmax (within two-fold). PBPK modelling can be used as a diagnostic tool to evaluate impaired mechanisms in HI.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149129085","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

Nanocarrier-Enabled Delivery of Glucosinolates for Skin Cancer Prevention and Therapy. 硫代葡萄糖苷的纳米载体递送用于皮肤癌的预防和治疗。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-10-07 DOI: 10.1208/s12248-026-01318-8

Chandrika Chaturvedi, Carman Giacomantonio, H P Vasantha Rupasinghe

{"title":"Nanocarrier-Enabled Delivery of Glucosinolates for Skin Cancer Prevention and Therapy.","authors":"Chandrika Chaturvedi, Carman Giacomantonio, H P Vasantha Rupasinghe","doi":"10.1208/s12248-026-01318-8","DOIUrl":"10.1208/s12248-026-01318-8","url":null,"abstract":"Skin cancer continues to pose a significant global health burden, with conventional therapeutic modalities limited by systemic toxicity, poor tumor selectivity, and the development of therapeutic resistance. Glucosinolates (GLs) and their hydrolyzed product, sulforaphane, have attracted considerable interest as chemopreventive and therapeutic agents owing to their potent antioxidant, anti-inflammatory, and pleiotropic anticancer activities. However, the clinical translation of these phytochemicals is severely hindered by their chemical instability, rapid metabolism, and poor bioavailability. Nanocarrier systems, particularly biodegradable polymeric nanoparticles such as poly(lactic-co-glycolic acid) nanoparticles, offer a promising strategy to overcome these barriers by enhancing compound stability, improving bioavailability, and enabling tumor-targeted delivery via the enhanced permeability and retention effect. This review critically evaluates recent progress in the development of GL and sulforaphane-loaded nanocarriers, detailing their physicochemical properties, in vitro and in vivo anticancer efficacy, and safety profiles, highlighting their potential to advance more effective and less toxic therapeutic strategies for skin cancer prevention and treatment.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128366","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

Statistical Tools for Biosimilarity Assessment: A Perspective Based on WHO-recommended Approaches. 生物相似性评估的统计工具：基于世卫组织推荐方法的视角。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-10-07 DOI: 10.1208/s12248-026-01304-0

Anurag S Rathore, Anuj Shrivastava

{"title":"Statistical Tools for Biosimilarity Assessment: A Perspective Based on WHO-recommended Approaches.","authors":"Anurag S Rathore, Anuj Shrivastava","doi":"10.1208/s12248-026-01304-0","DOIUrl":"10.1208/s12248-026-01304-0","url":null,"abstract":"Biosimilars expand access to biologic therapies by offering high quality, cost-effective alternatives to originator products. Analytical similarity assessment is central to biosimilar development, yet biosimilarity outcomes are strongly influenced by reference product (RP) lot numbers, assay variability and RP variability, and statistical methodology. The World Health Organization (WHO) recommends statistical tools for analytical biosimilarity evaluation, including X-sigma, min-max, and tolerance interval test, however their sensitivity to variability has not been systematically examined. In this perspective, we examine how reference lot selection, assay replication, and RP heterogeneity affect biosimilarity conclusions when applying WHO-recommended methods. Using analytical data across glycosylation, size heterogeneity, and charge variant, four biosimilars were compared with an innovator RP under different variability scenarios. Similarity outcomes were quantified using a normalized scoring framework. Increasing RP batches and incorporating broader intrinsic RP variability increased apparent biosimilarity by yielding acceptance limits that better reflected reference dataset dispersion, whereas limited sampling produced unstable variance estimates and restrictive criteria. Increased assay replication provided modest, attribute-dependent changes in biosimilarity outcomes. Across scenarios, X-sigma approaches were more robust to limited sampling and changes in variance estimates, whereas min-max and tolerance interval methods were more sensitive to dataset expansion and distributional extremes. These findings support data-driven justification of reference characterization and statistical strategy in biosimilarity assessment.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128503","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

Utilization of Brain Physiologically Based Pharmacokinetic Modeling in Support of CNS Drug Development: Case Example of Fenebrutinib. 基于脑生理学的药代动力学模型在支持中枢神经系统药物开发中的应用：以非尼布替尼为例。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-10-05 DOI: 10.1208/s12248-026-01277-0

Christine M Bowman, Fang Ma, Yan Xu, Denison Kuruvilla, Lin Pan, Matthew R Durk, Yuan Chen

{"title":"Utilization of Brain Physiologically Based Pharmacokinetic Modeling in Support of CNS Drug Development: Case Example of Fenebrutinib.","authors":"Christine M Bowman, Fang Ma, Yan Xu, Denison Kuruvilla, Lin Pan, Matthew R Durk, Yuan Chen","doi":"10.1208/s12248-026-01277-0","DOIUrl":"10.1208/s12248-026-01277-0","url":null,"abstract":"While accurately predicting the human brain penetration of drugs has been notoriously challenging, recent physiologically based pharmacokinetic (PBPK) modeling work has attempted to integrate passive permeability, active transport, and physiological parameters to support central nervous system (CNS) exposure predictions. In this study, a bottom-up PBPK approach was utilized prospectively to predict human cerebrospinal fluid (CSF) concentrations of fenebrutinib. In vitro permeability, efflux transporter, and brain binding data were generated and extrapolated in vitro to in vivo for required inputs in a five-compartment mechanistic brain PBPK model. The approach was first assessed using a compound with publicly available clinical CSF data, which informed the use of empirical scalars to address possible in vitro to in vivo translation gaps. The refined bottom-up PBPK approach was then used to predict the CSF concentrations of fenebrutinib. These predictions aligned well with observed CSF data as predicted values fell within 1.5 fold of the observed measurements, indicating the fenebrutinib has good brain penetration in multiple sclerosis (MS) patients, which were available afterward. This work demonstrates the utility of PBPK modeling to enable prospective CNS exposure prediction and support early clinical decision-making.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149118407","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

NCA Assistant: An Open-source R/Shiny Interface for Non-compartmental Pharmacokinetic Analysis, Bioequivalence Testing and Study Planning. NCA助手：一个开源的R/Shiny界面，用于非室室药代动力学分析，生物等效性测试和研究计划。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-28 DOI: 10.1208/s12248-026-01316-w

Rob Ter Heine

{"title":"NCA Assistant: An Open-source R/Shiny Interface for Non-compartmental Pharmacokinetic Analysis, Bioequivalence Testing and Study Planning.","authors":"Rob Ter Heine","doi":"10.1208/s12248-026-01316-w","DOIUrl":"10.1208/s12248-026-01316-w","url":null,"abstract":"Accessible tools for pharmacokinetic education and routine clinical pharmacokinetic analysis remain limited. Commercial software carries licensing costs and on the other hand existing open-source alternatives lack integrated workflows spanning study planning through bioequivalence assessment and are not user-friendly. We developed NCA Assistant, a browser-based application for non-compartmental pharmacokinetic analysis, bioequivalence testing, and power and sample size calculations within a single platform designed for pharmacokinetic research and teaching. NCA Assistant was designed with Anthropic Claude AI as coding assistant, with multi-expert prompting. The app was developed in R/Shiny with a hub-based architecture connecting six workflow modules. Core computations rely on established R packages for non-compartmental analysis, power and sample size calculations and analysis of variance. For the interface, there was an emphasis for transparency through interactive visualization, configurable analysis settings and exportable audit trails. The application supports extravascular and intravenous dosing scenarios, handles both single-subject and batch analyses and accommodates standard crossover, replicate, and parallel bioequivalence designs.A dedicated visualization module generates publication-ready concentration-time plots. Features include interactive terminal half-life review with point selection override and configurable thresholds for elimination half-life calculation. A validation package, consisting of draft validation documents and a validation script, accompanies the application and is supplied in the supplemental materials. NCA Assistant provides an accessible entry point for pharmacokinetic data analysis suitable for graduate training and routine clinical pharmacology applications, with extensibility for use in more regulated environments.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076620","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

Population Pharmacokinetics and Exposure-response Analysis of Durvalumab in Patients with Limited-stage Small-cell Lung Cancer in the Phase 3 ADRIATIC Study. 在3期亚得里亚海研究中，Durvalumab在有限期小细胞肺癌患者中的群体药代动力学和暴露反应分析。

IF 3.4 3区医学

AAPS Journal Pub Date : 2026-09-28 DOI: 10.1208/s12248-026-01295-y

Hong Su, Becky Jiajia Zhao, Yu Fu, Yan-Yan Zhang, Priti Chugh, Ed Casson, KyoungSoo Lim, Song Ren, Diansong Zhou, Peiming Ma, Chunling Fan

{"title":"Population Pharmacokinetics and Exposure-response Analysis of Durvalumab in Patients with Limited-stage Small-cell Lung Cancer in the Phase 3 ADRIATIC Study.","authors":"Hong Su, Becky Jiajia Zhao, Yu Fu, Yan-Yan Zhang, Priti Chugh, Ed Casson, KyoungSoo Lim, Song Ren, Diansong Zhou, Peiming Ma, Chunling Fan","doi":"10.1208/s12248-026-01295-y","DOIUrl":"10.1208/s12248-026-01295-y","url":null,"abstract":"Durvalumab monotherapy as a consolidation treatment for limited-stage small-cell lung cancer (LS-SCLC) demonstrated a favourable benefit-risk profile in the ADRIATIC study. We evaluated population pharmacokinetics (PopPK) and exposure-response (E-R) relationships of durvalumab in patients with LS-SCLC. The durvalumab PopPK model was updated by integrating PK data from the ADRIATIC study. Individual exposure metrics were derived from empirical Bayes estimates for E-R analyses relating to safety (adverse events [AEs]) and efficacy (progression-free survival [PFS] and overall survival [OS]). A two-compartment model with a time-dependent clearance adequately characterized durvalumab PK data. The typical parameter estimates for baseline clearance, central and peripheral volume of distribution were 0.273 L/day, 3.49 L and 2.35 L, respectively. All identified covariates are considered to have minimal clinical impact on durvalumab PK parameters with effect within 80-125% of typical values. Kaplan Meier plots of PFS or OS stratified by exposure quartiles suggested a plateaued relationship between durvalumab exposure and PFS or OS at the selected dose level of 1500 mg. The Cox PH model analysis did not identify exposure metrics as significant prognostic factors for the OS or PFS hazard. At 1500 mg IV Q4W, a flat E-R relationship was observed between durvalumab PK exposure and safety endpoints including Grade 3 + treatment-related AEs, Grade 3 + treatment-related AEs of special interest, and AEs leading to treatment discontinuation. The results support the use of durvalumab monotherapy for the patients with LS-SCLC, and no dose adjustment is considered necessary based on the PopPK and E-R analyses. NCT03703297.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149076644","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