AAPS 杂志是美国药物科学家协会 (AAPS) 的官方期刊，发表了影响人类和兽医治疗的药物科学各个领域的新颖而重要的发现，包括：· 药物设计和发现· 制药生物技术· 生物制药、制剂, 和药物递送· 代谢和运输· 药代动力学、药效学和药效学· 转化研究· 临床评估和治疗结果· 监管科学我们邀请以下文章类型提交：· 原创研究文章· 评论和小型评论· 白皮书、评论, 和社论· 会议报告· 简要/技术报告和快速通信· 监管说明· 教程· 药物科学协议此外，AAPS 期刊还发布由客座编辑组织的主题，重点关注我们领域当前感兴趣的特定领域.

AAPS Journal is the official journal of the American Association of Pharmaceutical Scientists (AAPS), publishing novel and significant findings across various fields of pharmaceutical science that impact human and veterinary therapeutics. The main topics include: drug design and discovery, pharmaceutical biotechnology, biopharmaceuticals, formulation and drug delivery, metabolism and transport, pharmacokinetics, pharmacodynamics, translational research, clinical evaluation and therapeutic outcomes, and regulatory science. We invite submissions of the following article types: original research articles, reviews and mini-reviews, white papers, commentaries and editorials, conference reports, brief/technical reports and rapid communications, regulatory guidelines, tutorials, and pharmaceutical science protocols. Additionally, AAPS Journal publishes themed issues organized by guest editors, focusing on specific areas of current interest in our field.

AAPS Journal 是美国药物科学家协会 (AAPS) 的官方期刊，发表影响人类和兽医治疗的药物科学各个领域的新颖而重要的发现。主要涵盖以下主题：药物设计与发现、制药生物技术、生物制药、制剂与药物递送、代谢与运输、药代动力学、药效学、转化研究、临床评估与治疗结果以及监管科学。我们欢迎以下类型的文章提交：原创研究文章、评论与小型评论、白皮书、评论与社论、会议报告、简要/技术报告与快速通信、监管说明、教程及药物科学协议。此外，AAPS Journal 还发布由客座编辑组织的主题，重点关注我们领域当前感兴趣的特定领域。

AAPS Journal

Over the past decade, artificial intelligence (AI) and machine learning (ML) have become the breakthrough technology most anticipated to have a transformative effect on pharmaceutical research and development (R&D). This is partially driven by revolutionary advances in computational technology and the parallel dissipation of previous constraints to the collection/processing of large volumes of data. Meanwhile, the cost of bringing new drugs to market and to patients has become prohibitively expensive. Recognizing these headwinds, AI/ML techniques are appealing to the pharmaceutical industry due to their automated nature, predictive capabilities, and the consequent expected increase in efficiency. ML approaches have been used in drug discovery over the past 15-20 years with increasing sophistication. The most recent aspect of drug development where positive disruption from AI/ML is starting to occur, is in clinical trial design, conduct, and analysis. The COVID-19 pandemic may further accelerate utilization of AI/ML in clinical trials due to an increased reliance on digital technology in clinical trial conduct. As we move towards a world where there is a growing integration of AI/ML into R&D, it is critical to get past the related buzz-words and noise. It is equally important to recognize that the scientific method is not obsolete when making inferences about data. Doing so will help in separating hope from hype and lead to informed decision-making on the optimal use of AI/ML in drug development. This manuscript aims to demystify key concepts, present use-cases and finally offer insights and a balanced view on the optimal use of AI/ML methods in R&D.

Sheela Kolluri

Jianchang Lin

Rachael Liu

Yanwei Zhang

Wenwen Zhang

The AAPS journal

AAPS J

Machine Learning and Artificial Intelligence in Pharmaceutical Research and Development: a Review.

机器学习与人工智能在药物研发中的应用：综述

The pharmaceutical industry is actively applying quantitative systems pharmacology (QSP) to make internal decisions and guide drug development. To facilitate the eventual development of a common framework for assessing the credibility of QSP models for clinical drug development, scientists from US Food and Drug Administration and the pharmaceutical industry organized a full-day virtual Scientific Exchange on July 1, 2020. An assessment form was used to ensure consistency in the evaluation process. Among the cases presented, QSP was applied to various therapeutic areas. Applications mostly focused on phase 2 dose selection. Model transparency, including details on expert knowledge and data used for model development, was identified as a major factor for robust model assessment. The case studies demonstrated some commonalities in the workflow of QSP model development, calibration, and validation but differ in the size, scope, and complexity of QSP models, in the acceptance criteria for model calibration and validation, and in the algorithms/approaches used for creating virtual patient populations. Though efforts are being made to build the credibility of QSP models and the confidence is increasing in applying QSP for internal decisions at the clinical stages of drug development, there are still many challenges facing QSP application to late stage drug development. The QSP community needs a strategic plan that includes the ability and flexibility to Adapt, to establish Common expectations for model Credibility needed to inform drug Labeling and patient care, and to AIM to achieve the goal (ACCLAIM).

Jane P. F. Bai

Brian J. Schmidt

Kapil G. Gadkar

Valeriu Damian

Justin C. Earp

Christina Friedrich

Piet H. van der Graaf

Rajanikanth Madabushi

Cynthia J. Musante

Kunal Naik

Mark Rogge

Hao Zhu

The AAPS Journal

FDA-Industry Scientific Exchange on assessing quantitative systems pharmacology models in clinical drug development: a meeting report, summary of challenges/gaps, and future perspective

FDA与制药业关于临床药物开发中定量系统药理学模型评估的科学交流：会议报告、挑战/差距总结及未来展望

The majority of drug candidates exhibit weakly basic characteristics with high lipophilicity. The risk of intraluminal compound precipitation has been studied in vivo and extensively in vitro using advanced dissolution transfer setups mimicking drug transfer from the stomach to the small intestine. The present investigation aims to evaluate the usefulness of the recently introduced Artificial Stomach-Duodenum in silico tool in the DDDPlusTM platform (ASD-D+) to simulate intraluminal drug behavior. The weakly basic drugs ketoconazole and dipyridamole were used as model drugs within the ASD-D+ model at two dose levels. The simulated amounts per volume were compared to intraluminal data collected from fasted healthy adults. Four different in silico transfer models running on a continuous or a stepwise mode were utilized for the simulations. Each transfer model exhibited different capabilities to simulate observed intraluminal drug presence. Three out of the four in silico models overestimated the total drug amount measured in vivo (dissolved and precipitated drug), while only two of the four models matched the intraluminal drug concentrations. The stepwise model enabled adequate simulations of both drug concentration and total drug amount. The present investigation highlighted the importance of simulating drug transfer appropriately within the applied methodology prior to estimating precipitation kinetics. As a future step, optimization of ASD-D+ model would enable evaluations of solid/semi-solid dosage form simulations. Lastly, prediction of drug precipitation kinetics following simulation of gastrointestinal transfer may provide mechanistic understanding of drug absorption and appropriate justification of drug-formulated parameters within physiologically based pharmacokinetic models.

Marina Statelova

Maria Vertzoni

Alexandros Kourentas

Simulation of Intraluminal Performance of Lipophilic Weak Bases in Fasted Healthy Adults Using DDDPlusTM

使用DDDPlusTM模拟禁食健康成年人体内亲脂性弱碱的管腔内表现

Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti-drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three-tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme. Depending on a biotherapeutic’s structural attributes, more characterization and testing may be appropriate. Unlike bioanalytical assays used to support the evaluation of pharmacokinetics or toxicokinetics, an important component in immunogenicity testing is the calculation of cut points for the identification (screening), confirmation (specificity), and titer assessment responses in animals and humans. Several key publications have laid an excellent foundation for statistical design and data analysis to determine immunogenicity cut points. Yet, the process for statistical determination of cut points remains a topic of active discussion by investigators who conduct immunogenicity assessments to support biotherapeutic drug development. In recent years, we have refined our statistical approach to address the challenges that have arisen due to the evolution in biotherapeutics and the analytical technologies used for quasi-quantitative detection. Based on this collective experience, we offer a simplified statistical analysis process and flow-scheme for cut point evaluations that should work in a large majority of projects to provide reliable estimates for the screening, confirmatory, and titering cut points.

Viswanath Devanarayan

Wendell C. Smith

Rocco L. Brunelle

Mary E. Seger

Kim Krug

Ronald R. Bowsher

Recommendations for Systematic Statistical Computation of Immunogenicity Cut Points

免疫原性截点系统统计计算的建议

Evolving immunogenicity assay performance expectations and a lack of harmonized anti-drug antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. Following debate at the American Association of Pharmaceutical Sciences National Biotechnology Conference, a group was formed to address these gaps. Over the last 3 years, 44 members from 29 organizations (including 5 members from Europe and 10 members from FDA) discussed gaps in understanding immunogenicity assay requirements and have developed harmonization tools for use by industry scientists to facilitate filings to health authorities. Herein, this team provides testing and reporting strategies and tools for the following assessments: (1) pre-study validation cut point; (2) in-study cut points, including procedures for applying cut points to mixed populations; (3) system suitability control criteria for in-study plate acceptance; (4) assay sensitivity, including the selection of an appropriate low positive control; (5) specificity, including drug and target tolerance; (6) sample stability that reflects sample storage and handling conditions; (7) assay selectivity to matrix components, including hemolytic, lipemic, and disease state matrices; (8) domain specificity for multi-domain therapeutics; (9) and minimum required dilution and extraction-based sample processing for titer reporting.

Heather Myler

João Pedras-Vasconcelos

Kelli Phillips

Charles Scott Hottenstein

Paul Chamberlain

Viswanath Devanaryan

Carol Gleason

Joanne Goodman

Marta Starcevic Manning

Shobha Purushothama

Susan Richards

Honglue Shen

Jad Zoghbi

Lakshmi Amaravadi

Troy Barger

Steven Bowen

Adrienne Clements-Egan

Dong Geng

Theresa J. Goletz

George R. Gunn

William Hallett

Michael E. Hodsdon

Brian M. Janelsins

Vibha Jawa

Szilard Kamondi

Susan Kirshner

Daniel Kramer

Meina Liang

Kathryn Lindley

Susana Liu

ZhenZhen Liu

Jim McNally

Alvydas Mikulskis

Robert Nelson

Mohsen Rajabi Ahbari

Qiang Qu

Jane Ruppel

Veerle Snoeck

An Song

Haoheng Yan

Mark Ware

Anti-drug Antibody Validation Testing and Reporting Harmonization

抗药物抗体验证检测与报告标准化

NH600001 is a new general anaesthetic drug with a structure similar to etomidate. The objective of this study was to investigate the relationship between concentrations of NH600001 and sedation efficacy based on data from phase I-II studies and factors influencing the pharmacokinetics and pharmacodynamics of NH600001. The dataset consisted of 2 phase I studies in healthy subjects and 1 phase II study in patients undergoing gastroscopy. Nonlinear mixed effects modeling was used in developing the population pharmacokinetics and pharmacodynamics (PopPK/PD) model of NH600001. Three-compartment model was used to describe the PK profile of NH600001. Parameters were used for allometric scaling on body weight, where the exponents were set to 0.75 for clearance and 1 for volumes. Co-administration of alfentanil hydrochloride influenced the distribution volume of the central compartment and clearance. Effect of patients undergoing gastroscopy (compared with healthy subjects) on clearance, the distribution volume of the superficial peripheral compartment and inter-compartmental clearance for deep peripheral compartment and central compartment was included the final PopPK model. The effect compartment model well characterized the PK/PD relationship of NH600001. Simulation results showed that an initial dose of 0.25 mg/kg of NH600001 resulted in rapid sedation, and three additional doses at 5-min intervals could maintain sedation for more than 20 min. A PopPK/PD model was successfully constructed for NH600001 in healthy subjects and in patients undergoing gastroscopy that could inform the dosing regimens of the forthcoming phase III study.

Yaxin Liu

Yun Kuang

Jie Huang

Dan Jiang

Yajie Cao

Qi Gao

Zifeng Li

Wen Ouyang

Saiying Wang

Qi Pei

Guoping Yang

Pharmacokinetic-pharmacodynamic Modelling of NH600001 in Healthy Subjects and Patients Undergoing Gastroscopy

NH600001在健康受试者和接受胃镜检查患者中的药代动力学-药效学建模

Abstract Characterizing and mitigating factors that impact product immunogenicity can aid in risk assessment and/or managing risk following manufacturing changes. For follow-on products that have the same indication, patient population, and active product ingredient, the residual immunogenicity risk resides predominantly on differences in product and process related impurities. Characterizing differences in innate immune modulating impurities (IIRMI), which could act as adjuvants by activating local antigen presenting cells (APCs), can inform the immunogenicity risk assessment potentially reducing the need for clinical trials. To date, assays to detect trace levels of IIRMI are being used to support regulatory decisions by FDA for selected synthetic peptide drug products that refer to reference listed drugs of rDNA origin but not recombinant protein or peptide products where more complex mixtures of trace impurities including host cell proteins are expected. Here we describe an exercise to explore whether or not there are differences in the innate immune response elicited by an insulin glargine (produced in E. coli ) and its interchangeable biosimilar insulin (produced in P. pastoris ) that could indicate differences in IIRMI. Our results suggest the two products elicit comparable innate immune responses as determined by the expression of 90 immune-related genes, including IL-1α, IL-1β, IL-6, CCL3, CCL2, and CXCL8. The data suggest that these assays can provide useful information when assessing recombinant proteins for the presence of IIRMI. Graphical Abstract

Cheng Her

Seth Thacker

Joseph Balsamo

Logan Kelley Baker

Derek DC Ireland

Eric Pang

Daniela Verthelyi

Cell-Based Assays to Detect Innate Immune Response Modulating Impurities: Application to Biosimilar Insulin

基于细胞的检测方法用于检测调节先天免疫反应的杂质：在生物类似药胰岛素中的应用

Spectroscopy (UV-visible, circular dichroism, infrared, Raman, fluorescence, etc.) is of fundamental importance to determine the structures of macromolecules and monitor their stability, especially for drug products, based on proteins or nucleic acids. In their 2014 article, Dinh et al. proposed Weighted Spectral Difference (WSD) as a method to quantitatively compute the dissimilarity of a given spectrum to a reference one. Despite the various properties of this method, its lack of symmetry and dependence on the selection of a reference limits the range of possible applications. Here, we propose a reference-free, symmetrized version of WSD (SWSD) that allows the computation of a semi-distance between two spectra. SWSD can be applied to perform group comparisons, track spectral kinetics, or construct a SWSD matrix leading to the hierarchical clustering of spectra. This method was tested on circular dichroism spectra from a split-virus-based (influenza) vaccine and a recombinant spike protein (COVID-19 vaccine). This approach resulted, first, in a perfect clustering of influenza A and B viruses into two distinct clusters, and second, in the detection of the change of secondary structure of the spike protein during a heating experiment, identifying two main temperatures of denaturation (Tm) by SWSD kinetics, in agreement with results obtained by conventional DSC. In summary, we have shown that SWSD is a versatile and efficient tool for quantitative spectral comparison, tracking spectral kinetics and enabling relevant unsupervised classification.

Karim Chouchane

Marina Kirkitadze

Rahul Misra

Przemyslaw Kowal

Olivier Dalloz-bourguignon

Frederic Greco

Sylvie Fayard

Sergio Marco

Didier Clenet

Quantitative Comparison and Clustering of Circular Dichroism Spectra Using a Symmetrized Weighted Spectral Difference

使用对称加权光谱差异对圆二色光谱进行定量比较和聚类

Abstract Per FDA guidance, method comparability should be established if an anti-drug antibody (ADA) assay is run by two or more independent laboratories during a study. Genentech, Inc. is evaluating an immunogenicity risk-based comparability approach consisting of both technical and clinical aspects. Technical comparability of the relative sensitivity (RS) is assessed using the Two One-Sided T-tests (TOST) statistical analysis which evaluates if the difference (in absolute value) of the RS means of the two laboratories is less than a pre-specified level of comparability, the practically significant difference (PSD). Clinical comparability is based on the molecule’s immunogenicity risk. A basic and in-depth assessment for low and high-risk molecules are used, respectively. An alternative strategy for molecules with limited incurred sample availability is to be used. In the basic assessment, samples are either unfortified or fortified with surrogate ADA positive control at method appropriate concentrations in a representative biological matrix. Acceptable comparability requires in both methods i) at least 80% of the unfortified samples screen and confirm negative, ii) at least 90% of the low concentration samples screen and confirm positive; and iii) 100% of the high concentration samples screen and confirm positive. The in-depth assessment uses at least 100 incurred samples from 30 or more ADA-positive and ADA-negative patients. The results are evaluated using a 2 by 2-confusion matrix and Cohen’s Kappa score where 1 indicates perfect agreement. Acceptable comparability requires a Cohen’s Kappa score of greater than 0.40. This strategy allows for a robust technical and clinical method comparability assessment. Graphical Abstract

R. J. Elliott

T. Pourmohamad

Y. Webb-Vargas

W. Yan

I. Nijem

P. Siguenza

Y. Song

Bioanalytical Method Comparison Strategy for Clinical Anti-drug Antibody Immunoassays

临床抗药抗体免疫分析的生物分析方法比较策略

Optimizing the interaction between antibody (mAb)-based therapeutics and immune effector functions (EFs) offers opportunities to improve the therapeutic window of these molecules. However, the role of EFs in antibody-drug conjugate (ADC) efficacy and toxicity remains unknown, with limited studies that have investigated how modulation of EF affects the pharmacology of ADCs. This study aimed to evaluate the effect of EF modulation on ADC efficacy using trastuzumab-vc-MMAE as a model ADC. A series of ADCs with enhanced or eradicated EF were synthesized through Fc engineering of the antibody. Cell-based assays confirmed that the alteration of EFs in ADCs did not change their in vitro potency, and the conjugation of vc-MMAE did not alter the trends in EFs modulation. Pharmacokinetic/pharmacodynamic (PK/PD) studies of Fc engineered ADCs were conducted in a syngeneic mouse system. The enhancement of EFs led to lower systemic exposure, faster clearance, and potentially enhanced tissue distribution and accumulation of ADCs. ADCs with enhanced EFs demonstrated improved efficacy in the syngeneic mouse tumor model, which was quantitatively confirmed by PK/PD modeling. The model indicated that EF enhancement was synergistic for ADC efficacy, whereas the complete removal of EF was less than additive. Our study suggests that developing ADCs with enhanced EF may improve the therapeutic effectiveness of ADCs, although the effect of this modification on ADC safety and extrapolation of our findings to other ADCs necessitates further investigation.

Hsuan-Ping Chang

Shufang Liu

Dhaval K. Shah

PK/PD Evaluation of Antibody–Drug Conjugates with Enhanced Immune Effector Functions

具有增强免疫效应功能的抗体-药物偶联物的药代动力学/药效学评价

Abbreviation	AAPS J
Journal Impact	5.17
Quartiles(Global)	PHARMACOLOGY & PHARMACY(Q1)

ISSN	1550-7416
h-index	132

Publication Information	Publisher: Springer New York，Publishing cycle: Quarterly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1999，Proportion of original research papers: 81.25%，Self Citation Rate:4.00%， Gold OA Rate: 33.33%
Average review cycle	网友分享经验：平均1.0个月

AAPS Journal

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