AAPS Journal最新文献_第3页

A Bottom-up Approach for Mutant and Wild Type Collies Using Physiologically Based Pharmacokinetic (PBPK) Modeling: A Case Study Using Loperamide. 基于生理药代动力学（PBPK）建模的突变型和野生型牧羊犬自下而上方法：以洛哌丁胺为例研究。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-02 DOI: 10.1208/s12248-025-01061-6

Charlotte Cross, Marilyn N Martinez, Devendra Pade, Michael J Myers, Sibylle Neuhoff

{"title":"A Bottom-up Approach for Mutant and Wild Type Collies Using Physiologically Based Pharmacokinetic (PBPK) Modeling: A Case Study Using Loperamide.","authors":"Charlotte Cross, Marilyn N Martinez, Devendra Pade, Michael J Myers, Sibylle Neuhoff","doi":"10.1208/s12248-025-01061-6","DOIUrl":"10.1208/s12248-025-01061-6","url":null,"abstract":"A bottom-up physiologically based pharmacokinetic (PBPK) model was developed to predict the pharmacokinetics of loperamide, a substrate for multidrug resistance 1 (Mdr1) encoded P-glycoprotein (P-gp), in wild-type dogs (WT) and dogs that are homozygous for a base-pair deletion in the Mdr1 gene encoding for P-gp (Mu, Δ-Mdr1). In vitro-to-in vivo extrapolation (IVIVE) techniques were employed where in vitro data describing loperamide absorption, distribution, metabolism, and elimination (ADME) were extrapolated to in vivo dose exposure predictions. Importantly, by applying system parameters extrapolated from other breeds and published information on Collie-specific physiology, for the first time, a breed-specific whole-body PBPK model for the Collie was developed. Using our loperamide IVIVE-PBPK model (Simcyp Animal Simulator), the observed plasma concentration-versus-time profiles after intravenous and oral loperamide administration were successfully captured. The overall model performance for the WT (n = 7) and Mu (n = 10) Collies was within 1.40 and 1.24, and 1.18 and 1.51 AAFE for the Area under the plasma concentration-time-profile curve (AUC)0-24 h and maximal plasma concentration (Cmax) predictions, respectively. Predicted Cmax values were within ± 25% of observed values for 67% of all doses for the WT dogs. For the Mu dogs, the predicted AUC0-24 h was within 50% for all doses. Our work provides the first example of a systematic approach for Collies and illustrates its use to describe the impact of a known genetic variation in the canine Mdr1 gene. Furthermore, we describe the general workflow for establishing, verifying, and applying an IVIVE-PBPK framework for predicting in vivo drug behavior within a specific canine breed.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"101"},"PeriodicalIF":5.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210129","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 Impact of AI-Based Model-Informed Drug Development (MIDD): A Comparative Review. 评估基于人工智能模型的药物开发（MIDD）的影响：一项比较综述。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-02 DOI: 10.1208/s12248-025-01075-0

Bingyu Mao, Yue Gao, Christine Xu, Sreeraj Macha, Shuai Shao, Malidi Ahamadi

{"title":"Evaluating the Impact of AI-Based Model-Informed Drug Development (MIDD): A Comparative Review.","authors":"Bingyu Mao, Yue Gao, Christine Xu, Sreeraj Macha, Shuai Shao, Malidi Ahamadi","doi":"10.1208/s12248-025-01075-0","DOIUrl":"10.1208/s12248-025-01075-0","url":null,"abstract":"Model-informed drug development (MIDD) methods play critical role to ensure development of efficacious, and safe individualized therapies. The application of artificial intelligence/machine learning (AI/ML) within the field of drug development has exponentially expanded. Integrating AI/ML into traditional pharmacometrics approaches or using AI/ML as a stand-alone tool has the potential to optimize dosing strategies, inform clinical trial designs, and enhance robustness of quantitative assessments of drug efficacy and safety. This review systematically evaluates the impact of AI-based model-informed drug development (MIDD) methods compared to traditional approaches by blending regulatory perspectives. We conducted a systematic search on PubMed using five Medical Subject Headings (MeSH) terms and included 67 relevant studies in the analysis. The results indicate that AI models have the potential of improving MIDD approaches through different stages of drug development to inform decision-making in clinical trials. However, limitations such as the lack of standardized evaluation metrics and standardized regulatory guidelines on the use of AI-based MIDD methods were noted. Overall, this review highlights the potential applications of AI in drug development and provides a foundation for future research to optimize and integrate AI-based approaches in this field.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"102"},"PeriodicalIF":5.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210175","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 Comparative Study on Physicochemical and Analytical Characterizations of Doxil® and its Generic Drug Products. Doxil®及其仿制药理化及分析特性的比较研究。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-02 DOI: 10.1208/s12248-025-01058-1

Adaeze Eneli, Kaikai Wang, Jingyao Gan, Rimpy Diwan, Ziyi Lu, Minzhi Yu, Rose Ackermann, Brian Shay, Anna Schwendeman

{"title":"A Comparative Study on Physicochemical and Analytical Characterizations of Doxil® and its Generic Drug Products.","authors":"Adaeze Eneli, Kaikai Wang, Jingyao Gan, Rimpy Diwan, Ziyi Lu, Minzhi Yu, Rose Ackermann, Brian Shay, Anna Schwendeman","doi":"10.1208/s12248-025-01058-1","DOIUrl":"10.1208/s12248-025-01058-1","url":null,"abstract":"Doxil®, a PEGylated liposomal doxorubicin (DOX) hydrochloride suspension, was the first liposome drug product approved by the U.S. Food and Drug Administration (FDA). Although off-patent, limited generic products have been approved due to challenges in achieving bioequivalence compounded by manufacturing complexity. Regulatory agencies require generic drug products to be bioequivalent to the reference listed drug. In this regard, we developed various analytical methods to analyze Doxil® and its generic drug products for multiple attributes, including liposome size distribution, zeta potential, DOX content, lipid content, purity, non-encapsulated doxorubicin, morphology, nanostructure similarity, and quantified in vitro release. Batch-to-batch variation exists across attributes for different formulations. Minor differences in particle size and zeta potential were observed. Cryo-TEM imaging reveals the distinct coffee bean shape and morphology of the Doxil® liposome. SAXS similarity analysis shows a distinct difference in nanostructure for Dr. Reddy's formulation compared to the innovator formulation. Still, it is revealed to be a consequence of liposome uniformity and homogeneity as depicted in cryo-TEM images. Several methods developed in this work can be complementary to provide a more thorough physicochemical analysis for generic evaluation. Size, morphology, and nanostructure evaluated by DLS, cryo-TEM, and SAXS should be readily employed to assess physicochemical similarity. Content, impurity identification, and amount of free non-encapsulated DOX are used to evaluate formulation sameness. The methods developed in this work provide a physicochemical framework for analytical comparison of complex liposomal generics and may support subsequent development efforts to improve generic drug availability for patient populations in need.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"100"},"PeriodicalIF":5.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210130","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

Publisher Correction: Generating Realistic Albumin Concentrations in Virtual Subjects Across A Spectrum of Renal Function to Account for Variability in Protein Binding Within PBPK Models. 出版者更正：在虚拟受试者中产生真实的白蛋白浓度，跨越肾功能谱，以解释PBPK模型中蛋白质结合的变异性。

IF 5 3区医学

AAPS Journal Pub Date : 2025-05-28 DOI: 10.1208/s12248-025-01089-8

Yuming Hu, Daniel Scotcher

引用次数: 0

Risk Assessment for Biopharmaceutics Classification System Class IV Molecule Containing Immediate Release Products: Use of In-Silico Prediction Tools and Physiologically Based Pharmacokinetic Modeling. 生物制药分类系统IV类分子含立即释放产品的风险评估：使用计算机预测工具和基于生理的药代动力学建模。

IF 5 3区医学

AAPS Journal Pub Date : 2025-05-28 DOI: 10.1208/s12248-025-01086-x

Sivacharan Kollipara, Mahendra Chougule, Karthik Parsa, Priyansh Pandya, Tausif Ahmed

{"title":"Risk Assessment for Biopharmaceutics Classification System Class IV Molecule Containing Immediate Release Products: Use of In-Silico Prediction Tools and Physiologically Based Pharmacokinetic Modeling.","authors":"Sivacharan Kollipara, Mahendra Chougule, Karthik Parsa, Priyansh Pandya, Tausif Ahmed","doi":"10.1208/s12248-025-01086-x","DOIUrl":"10.1208/s12248-025-01086-x","url":null,"abstract":"Nitrosamines drug substance related impurities (NDSRI) are organic impurities, highly potent mutagenic substances that are classified as human carcinogens. Regulatory guidance's in this area provide procedures for control and risk mitigation of NDSRI's in drug products. While efforts are made to control the NDSRI's, cases where NDSRI's are observed post- pivotal bioequivalence studies may require additional bioequivalence studies, between pre- and post- change formulations. The recent USFDA (United State Food and Drug Administration) guidance on \"Control of Nitrosamine Impurities in Human Drugs\" provides alternative BE methodologies for biopharmaceutics classification system (BCS) I, II and III drugs based on in vitro testing. For BCS IV molecule containing immediate release (IR) formulations, physiologically based pharmacokinetic (PBPK) modeling approach is recommended. In this context, this present article discusses use of PBPK modeling approaches as alternative BE methodologies for BCS IV molecule containing IR products. We have summarized use of in-house in silico tool for early risk prediction of NDSRI's solely based on molecule structure. This tool was used to predict the carcinogenic potential of 37 BCS IV molecules and further clinical exposure risk assessment was conducted on identified 5 high risk category molecules namely edoxaban, selumetinib, bosutinib, furosemide, hydrochlorothiazide where transporters are involved in absorption. The PBPK models were used to evaluate the impact of altered permeability and transporter kinetics on exposures, that may happen in presence of antioxidants. Further, the impact of permeability within ± 10-20% was evaluated on clinical exposures to determine permeability safe space (region within which bioequivalence is guaranteed as compared to the target formulation).","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"97"},"PeriodicalIF":5.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163607","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 Real-World Evidence to Support FDA Regulatory Decision Making. 应用真实世界证据支持FDA监管决策。

IF 5 3区医学

AAPS Journal Pub Date : 2025-05-28 DOI: 10.1208/s12248-025-01082-1

Vipada Khaowroongrueng, Tae-Eun Kim, Sang-In Park, Kwang-Hee Shin

{"title":"Application of Real-World Evidence to Support FDA Regulatory Decision Making.","authors":"Vipada Khaowroongrueng, Tae-Eun Kim, Sang-In Park, Kwang-Hee Shin","doi":"10.1208/s12248-025-01082-1","DOIUrl":"10.1208/s12248-025-01082-1","url":null,"abstract":"Real-world data (RWD) and real-world evidence (RWE) are valuable resources for drug development strategies. Historically, it has been used for safety evaluation during post-marketing surveillance. RWD and RWE have been utilized in the regulatory decision-making process for drug effectiveness, especially for rare diseases and cancers, where conducting randomized controlled trials is challenging. The Food and Drug Administration (FDA) is actively working on providing trustworthy information derived from RWD and RWE to supplement the data from clinical trials. This review discusses the potential use of RWE to make regulatory decisions on drug effectiveness for certain therapeutic areas as well as the challenges in drawing inferences on drug effectiveness from RWE. A review of FDA-approved new drug applications and biologics license applications suggests that several methodological considerations should be deliberated when designing a study using RWE to demonstrate product effectiveness. The acceptance of RWE, while promising, is dependent on the relevance and reliability of the data. The insight and engagement of all stakeholders contribute to the successful use of RWE for clinical evaluations.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"98"},"PeriodicalIF":5.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175646","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

Rethinking Pharmaceutical Industry with Quality by Design: Application in Research, Development, Manufacturing, and Quality Assurance. 以设计反思制药工业的质量：在研究、开发、制造和质量保证中的应用。

IF 5 3区医学

AAPS Journal Pub Date : 2025-05-20 DOI: 10.1208/s12248-025-01079-w

Joana Galvão Duarte, Maria Galvão Duarte, Ana Paula Piedade, Filipa Mascarenhas-Melo

{"title":"Rethinking Pharmaceutical Industry with Quality by Design: Application in Research, Development, Manufacturing, and Quality Assurance.","authors":"Joana Galvão Duarte, Maria Galvão Duarte, Ana Paula Piedade, Filipa Mascarenhas-Melo","doi":"10.1208/s12248-025-01079-w","DOIUrl":"10.1208/s12248-025-01079-w","url":null,"abstract":"Quality by Design (QbD) is a transformative and systematic approach to developing top-tier pharmaceutical products, ushering in a departure from traditional trial-and-error methods toward a more science-based, risk-oriented, and holistic strategy. Central to QbD implementation is the meticulous development of formulations and manufacturing processes, consistently fulfilling predefined quality objectives. The core objective of QbD remains unwavering - to guarantee the steadfast alignment of the final pharmaceutical product with predetermined quality attributes, thereby mitigating batch-to-batch variations and potential recalls. This article succinctly explores the multifaceted application of QbD methodology within the pharmaceutical industry. Emphasizing its pivotal role in research and development, manufacturing, quality control, and quality assurance, the discussion navigates through the strategic deployment of QbD elements and tools. Amidst the evident advantages of QbD, challenges persist in its widespread adoption within the pharmaceutical sector and regulatory frameworks. This article sheds light on the regulatory landscape that currently governs the implementation of QbD in these crucial stages of pharmaceutical processes. For that reason, this review article aims to provide researchers, scientists, and industry professionals with a thorough introduction to QbD so they may adopt this methodical approach to developing and producing high-quality pharmaceutical products, always in compliance with the underlying regulations.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"96"},"PeriodicalIF":5.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103061","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

Improvement of Drug Release from an Aptamer Drug Conjugate Using Reductive-sensitive Linkers for Tumor-targeted Drug Delivery. 利用还原敏感连接体改善适体药物偶联物在肿瘤靶向药物递送中的药物释放。

IF 5 3区医学

AAPS Journal Pub Date : 2025-05-20 DOI: 10.1208/s12248-025-01070-5

You Wu, Yusuke Kawamoto, Jin Sun, Yuki Takahashi, Yuriko Higuchi, Yoshinobu Takakura

{"title":"Improvement of Drug Release from an Aptamer Drug Conjugate Using Reductive-sensitive Linkers for Tumor-targeted Drug Delivery.","authors":"You Wu, Yusuke Kawamoto, Jin Sun, Yuki Takahashi, Yuriko Higuchi, Yoshinobu Takakura","doi":"10.1208/s12248-025-01070-5","DOIUrl":"10.1208/s12248-025-01070-5","url":null,"abstract":"The selective delivery of small molecule compounds such as Gemcitabine to tumor cells is a promising methodology for enhancing therapeutic efficacy and attenuating the side effects of anticancer drugs. Aptamers are useful as target-directed ligands for tumor-selective drug delivery due to their ability to bind specific proteins. However, the drug must be released from the aptamer after the conjugate is taken up by the cell to exert its pharmacological effect. In this study, we designed and synthesized a conjugate in which a linker cleaved by glutathione, which is highly expressed in tumor cells, was inserted between the aptamer (AS1411) and Gemcitabine. Almost all Gemcitabine was released from the conjugate after 30 min in the presence of 6 mM glutathione. AS1411 is known to bind to nucleolin, which is highly expressed on tumor cells. The cytotoxicity of the AS1411 and Gemcitabine conjugate with a disulfide bond on A549 cells was higher than that of the conjugate without a disulfide bond. Furthermore, the cytotoxicity of the disulfide-linked conjugate of AS1411 and Gemcitabine was higher in A549 cells than in MCF10A cells, which were used as the model of normal cells. These results indicate that disulfide conjugation enhanced the tumor cell-selective cytotoxicity of Gemcitabine with AS1411.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"95"},"PeriodicalIF":5.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112695","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

Short-Term Immunosuppression in Rats Induces Prolonged Immune Tolerance Towards a Human Monoclonal Antibody, Erenumab. 大鼠短期免疫抑制诱导对人单克隆抗体Erenumab的长期免疫耐受。

IF 5 3区医学

AAPS Journal Pub Date : 2025-05-16 DOI: 10.1208/s12248-025-01083-0

Paridhi Gupta, Ashish Srivastava, Josiah T Ryman, Michael D Swanson, Alexander Kozhich, Vibha Jawa, Bernd Meibohm

{"title":"Short-Term Immunosuppression in Rats Induces Prolonged Immune Tolerance Towards a Human Monoclonal Antibody, Erenumab.","authors":"Paridhi Gupta, Ashish Srivastava, Josiah T Ryman, Michael D Swanson, Alexander Kozhich, Vibha Jawa, Bernd Meibohm","doi":"10.1208/s12248-025-01083-0","DOIUrl":"10.1208/s12248-025-01083-0","url":null,"abstract":"Administration of human therapeutic proteins such as monoclonal antibodies (mAb) to animals during preclinical drug development often leads to the development of anti-drug antibodies (ADA). ADA may reduce the systemic exposure of the mAb by enhancing its immune-complex mediated clearance. Thus, ADA may hinder the preclinical pharmacokinetic and toxicology assessments of mAbs. To mitigate this effect, we explored the ability of short-term administration of immunosuppressants to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. In two studies, we investigated dosing regimens using the immunosuppressants methotrexate and tacrolimus/sirolimus combination, and compared them to non-immunosuppressed control groups. Each study comprised three phases: induction (weeks 1-4), washout (weeks 5-8), and rechallenge (weeks 9-12). Animals received mAb during the induction and rechallenge phase, while immunosuppression was limited to the induction and washout phase. Blood samples were collected at predefined time-points for erenumab and ADA quantification. The tacrolimus/sirolimus regimen, but not the tested methotrexate regimens, completely prevented ADA formation in all treated animals relative to the control groups. The tacrolimus/sirolimus treated animals not only remained ADA-negative with initial immunosuppression during the induction phase but remained ADA-negative even after erenumab rechallenge suggesting the induction of immune-tolerance beyond the immunosuppressive treatment period. Correspondingly, erenumab systemic exposures were maintained throughout the study period in all animals in the tacrolimus/sirolimus group and were similar to the erenumab exposures in ADA-negative animals of the control group. In contrast, ADA-positive animals in the control group exhibited a 60-80% reduction in erenumab exposures.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"94"},"PeriodicalIF":5.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144087000","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

Publisher Correction: Simultaneous Estimation of fm and FG Values Directly from Clinical Drug-Drug Interaction Study Data. 出版者更正：直接从临床药物-药物相互作用研究数据中同时估计fm和FG值。

IF 5 3区医学

AAPS Journal Pub Date : 2025-05-16 DOI: 10.1208/s12248-025-01081-2

Yumi Cleary, Nicolo Milani, Kayode Ogungbenro, Leon Aarons, Aleksandra Galetin, Michael Gertz

引用次数: 0