Practice of model-informed drug development in pharmaceutical in-dustry in China / 中国临床药理学与治疗学

Guideline of model-informed drug de-velopment was published by National Medical Products Administration in 2020,which provided technical guidance for the application of modeling and simulation in the process of new drug develop-ment.In July 2022,Center of Drug Evaluation con-ducted a questionnaire survey on the practical abili-ty of pharmaceutical industry to apply model-in-formed drug development(MIDD)in the process of new drug development,in order to investigate the practice of MIDD in China.Based on the feedback data collected from enterprises,this paper analyzes the practice of MIDD in domestic pharmaceutical industry,and briefly discusses several problems that still exist at present.

Development on Cancer Therapeutic Drugs Approved by FDA in 2023 / 肿瘤防治研究

Since the beginning of the 21st century, the field of cancer drug development has undergone significant changes. Kinase inhibitors are the product category with the highest number of approved drugs and indications. However, despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product categories. In the year of 2023, the FDA’s Center for Drug Evaluation and Research (CDER) has approved 13 new cancer therapeutic drugs. In the past five years, a slight increase in drug approvals targeting biomarker-defined populations as well as emerging approvals that are agnostic to tumor anatomy has been recorded. Currently, new treatment approaches and technologies, such as the development of Artificial Intelligence (AI), have increasingly profound progress on cancer drug development.

Real World Data Use in Pharmaceutical Companies in Japan： Current Status and Issues from Survey of Japan Pharmaceutical Manufacturers Association / 薬剤疫学

Objective：To investigate the purposes, reasons, and issues of Real World Data (RWD) utilization by data source among pharmaceutical companies in Japan. In this study, we focus on RWDs such as Electronic Medical Records (EMR), Personal Health Records, and registries, which are expected to be utilized in the future. Design：Web based-questionnaire surveyMethods：This questionnaire survey was conducted on 68 companies affiliated with Clinical Evaluation Expert Committee in Japan Pharmaceutical Manufacturers Association from January 18th to February 14th in 2022. In principle, the survey covered four divisions (Clinical development, Pharmacovigilance, Medical Affairs, Health Economics & Outcomes Research) of each company, and other cross-functional divisions were also acceptable to answer. Results：［Background］ Of 40 companies out of 68 companies, 102 respondents were responded to this survey. Overall, 75 respondents (73.5％) have “experienced in utilization of RWD”, and 12 (11.8％) have “experienced in considering utilization of RWD”. ［Utilization by RWD Type］ By data source, hospital-based claim data was the most frequently used (65 cases, 63.7％), followed by insurance-based claim data (61 cases, 59.8％), surveys (38 cases, 37.3％), and EMR (36 cases, 35.3％) in experienced RWD utilization. Conclusion：This study revealed the current status and issues related to the utilization of each type of RWDs in Japan. It is expected that data linkage among multiple RWDs and data standardization enable further utilization of RWDs in future.

Real World Data Use in Pharmaceutical Companies in Japan： Current Status and Issues from Survey of Japan Pharmaceutical Manufacturers Association / 薬剤疫学

Objective：To investigate the purposes, reasons, and issues of Real World Data (RWD) utilization by data source among pharmaceutical companies in Japan. In this study, we focus on RWDs such as Electronic Medical Records (EMR), Personal Health Records, and registries, which are expected to be utilized in the future. Design：Web based-questionnaire surveyMethods：This questionnaire survey was conducted on 68 companies affiliated with Clinical Evaluation Expert Committee in Japan Pharmaceutical Manufacturers Association from January 18th to February 14th in 2022. In principle, the survey covered four divisions (Clinical development, Pharmacovigilance, Medical Affairs, Health Economics & Outcomes Research) of each company, and other cross-functional divisions were also acceptable to answer. Results：［Background］ Of 40 companies out of 68 companies, 102 respondents were responded to this survey. Overall, 75 respondents (73.5％) have “experienced in utilization of RWD”, and 12 (11.8％) have “experienced in considering utilization of RWD”. ［Utilization by RWD Type］ By data source, hospital-based claim data was the most frequently used (65 cases, 63.7％), followed by insurance-based claim data (61 cases, 59.8％), surveys (38 cases, 37.3％), and EMR (36 cases, 35.3％) in experienced RWD utilization. Conclusion：This study revealed the current status and issues related to the utilization of each type of RWDs in Japan. It is expected that data linkage among multiple RWDs and data standardization enable further utilization of RWDs in future.

Application status and development trend of virtual clinical trials / 中国胸心血管外科临床杂志

@#Virtual clinical trials are clinical trials conducted through computer simulation technology, which breaks through the limitations of traditional clinical trials and has the advantages of saving time, reducing costs, and reducing the risk of human trials. With the application of new computer technologies such as population pharmacokinetics, physiologically-based pharmacokinetics, quantitative systems pharmacology, and artificial intelligence, the field of virtual clinical trials in healthcare has become an important development direction. This article will give a preliminary review of the connotation, methods and future development trends of virtual clinical trials, aiming to provide reference for the application of new technologies and methods in clinical trials.

Knowledge of elementary and high school students about experimental animal research / Conocimiento de los alumnos de la primaria y la secundaria sobre investigación experimentalen animales / Conhecimento de alunos dos ensinos fundamental e médio sobre pesquisa experimental em animais

Abstract Experimental research with the use of animal models to represent a specific reality is a target of criticism by the population. This study analyzed the knowledge of elementary and high school students on experimental/animal research methods, official ethical guidelines/laws, and regulatory institutions. In total, 35 students answered an informative questionnaire with objective questions about the subject. Only 18 students (Group 1), attended a lecture on the subject. The questionnaire was reapplied to all 35 students. The analysis of the first questionnaire round showed rejection by 51.4% of the students toward the methods used in experimental research. Significant changes in answer patterns between the first and second evaluations were observed, with a decrease in the number of students who strongly disagree with the methods used in experimental research in Group 1 (38.8%) compared to Group 2 (88.2%). These data suggest that educational activities could increase the acceptance of experimental research by the community.

Resumen La investigación experimental en animales para representar una realidad específica es criticada por la población. Este estudio analizó el conocimiento de los alumnos de la primaria y la secundaria sobre los métodos de investigación experimental/animal, los lineamientos/leyes éticas oficiales e instituciones que reglamentan. Un cuestionario con preguntas objetivas sobre el tema fue respondido por 35 alumnos. Solo 18 alumnos (Grupo 1) asistieron a una conferencia sobre el tema. El cuestionario se aplicó nuevamente a 35 alumnos. El primer cuestionario mostró que el 51,4% de los alumnos rechazaban los métodos utilizados en la investigación experimental. Hubo cambios significativos en las respuestas entre la primera y la segunda evaluación, con menor número de alumnos que estaban totalmente en desacuerdo con los métodos de la investigación experimental en el Grupo 1 (38,8%) en comparación con el Grupo 2 (88,2%). Por tanto, las actividades educativas pueden incrementar la aceptación comunitaria de la investigación experimental.

Resumo A pesquisa experimental com uso de modelos animais para representar uma realidade específica é alvo de críticas por parte da população. Este estudo analisou o conhecimento de alunos do ensino fundamental e médio sobre métodos de pesquisa experimental/animal, diretrizes/leis éticas oficiais e instituições reguladoras. Ao todo, 35 alunos responderam a um questionário informativo com perguntas objetivas sobre o assunto. Apenas 18 alunos (Grupo 1) assistiram a uma palestra sobre o tema. O questionário foi aplicado novamente aos 35 alunos. A análise do primeiro questionário mostrou rejeição por 51,4% dos estudantes em relação aos métodos utilizados na pesquisa experimental. Observaram-se mudanças significativas nos padrões de resposta entre a primeira e a segunda avaliação, com diminuição do número de alunos que discordam totalmente dos métodos utilizados na pesquisa experimental no Grupo 1 (38,8%) em relação ao Grupo 2 (88,2%). Esses dados sugerem que atividades educativas podem aumentar a aceitação da pesquisa experimental pela comunidade.

The history and rationale of the development of new drugs for migraine treatment / A história e os fundamentos do desenvolvimento de novos medicamentos para o tratamento da migrânea

Abstract Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen its individual, social, and economic impact. This is a narrative review of the main drugs used for treating migraine, as well as the experimental models and the theoretical frameworks that led to their development. Ergot derivatives, triptans, non-steroid anti-inflammatory drugs, tricyclic antidepressants, beta-blockers, flunarizine, valproic acid, topiramate, onabotulinumtoxin A, ditans, monoclonal antibodies against CGRP and its receptor, and gepants are discussed. Possible therapeutic targets for the development of new drugs that are under development are also addressed. Many of the drugs currently in use for treating migraine were developed for the treatment of other diseases, but have proven effective for the treatment of migraine, expanding knowledge about the disease. With a better understanding of the pathophysiology of migraine, new drugs have been and continue to be developed specifically for the treatment of this disease.

Resumo A migrânea é uma das doenças mais prevalentes e incapacitantes do mundo. O tratamento da crise de migrânea e o tratamento profilático da doença são essenciais para diminuir o seu impacto individual, social e econômico. Este é um artigo de revisão narrativa. Revisamos as principais drogas usadas para a migrânea e os modelos experimentais e referenciais teóricos que levaram ao seu desenvolvimento. Foram abordados os derivados do ergot, triptanas, anti-inflamatórios não hormonais, antidepressivos tricíclicos, betabloqueadores, flunarizina, ácido valproico, topiramato, toxina onabotulínica do tipo A, os ditans, anticorpos monoclonais contra o CGRP e seu receptor e os gepants. Também foram abordados possíveis alvos terapêuticos para o desenvolvimento de novas drogas e drogas que estão em desenvolvimento para o tratamento da migrânea. Muitas das drogas usadas atualmente foram desenvolvidas para o tratamento de outras doenças e se mostraram efetivas para o tratamento da migrânea. Essas ajudaram a ampliar o conhecimento sobre a doença. Com o melhor entendimento da fisiopatologia da migrânea, novas drogas foram e estão sendo desenvolvidas especificamente para o tratamento dessa doença.

ADMET, Pharmacokinetic and Docking properties of the fungal drug 2- (2, 4-difluorophenyl)-1, 3-bis (1, 2, 4-triazol-1-yl) propan-2-ol by using Quantum computational methods

The current study contributes to a better knowledge of the FCZ's characteristics and bioactivity. The ADMET properties have been calculated and the results have been illustrated; as a result, it has become quite popular for virtual pharmaceutical analysis. This research aims to examine FCZ’s optimized structure and properties by analyzing various computational calculations. Bond length, Bond angle, Mulliken charges have been analyzed for the studies. The experimental geometrical parameters and theoretical data were compared with ADME parameters, biomarker properties, pH value, drug like nature, Marvin sketch, Swiss ADME to quantify molecular descriptors just as to survey atomic elements. ADMET properties introduce the influence of the drug levels and its kinetics with the tissues of the body. It also explains about the metabolism, toxicity of the drugs when introduced to the system. The analysis on pharmacokinetic properties has helped a lot in the drug development for further studies. The target prediction of FCZ has been studied along with the docking study. Docking study is an important program in order to study about the binding of the small ligand into a receptor like proteins. This method is very useful in drug discovery which provides insights into various studies. This will help in further development of the drugs which will finally help the society in large scale. FCZ helps pharmaceutical industry in developing the drugs to treat chronic disease when combined with other molecules. Hence the present study is really helpful in drug designing and in the development of new drugs.

Update of the Brazilian consensus recommendations on Duchenne muscular dystrophy / Atualização das recomendações do consenso brasileiro para distrofia muscular de Duchenne

Abstract In the last few decades, there have been considerable improvements in the diagnosis and care of Duchenne muscular dystrophy (DMD), the most common childhood muscular dystrophy. International guidelines have been published and recently reviewed. A group of Brazilian experts has developed a standard of care based on a literature review with evidence-based graded recommendations in a two-part publication. Implementing best practice management has helped change the natural history of this chronic progressive disorder, in which the life expectancy for children of the male sex in the past used to be very limited. Since the previous publication, diagnosis, steroid treatment, rehabilitation, and systemic care have gained more significant insights with new original work in certain fields. Furthermore, the development of new drugs is ongoing, and some interventions have been approved for use in certain countries. Therefore, we have identified the need to review the previous care recommendations for Brazilian patients with DMD. Our objective was to create an evidence-based document that is an update on our previous consensus on those topics.

Resumo Nas últimas décadas, houve progressos significativos no diagnóstico e no tratamento da distrofia muscular de Duchenne (DMD), considerada a distrofia muscular mais comum na infância. Diretrizes internacionais foram publicadas e revisadas recentemente. Um grupo de especialistas brasileiros desenvolveu um padrão de atendimento baseado em revisão de literatura, com recomendações graduadas pautadas em evidências compiladas em uma publicação dividida em duas partes. A implementação de melhores práticas de manejo ajudou a modificar a história natural desta doença crônica, progressiva, que, no passado, oferecia uma expectativa de vida muito limitada para crianças do sexo masculino. Desde a publicação desse consenso anterior, o diagnóstico, o tratamento com esteroides, a reabilitação e os cuidados sistêmicos ganharam novas possibilidades a partir da divulgação dos resultados de trabalhos originais em algumas dessas áreas. Além disso, as pesquisas e o desenvolvimento de novos fármacos estão em andamento, e algumas intervenções já foram aprovadas para uso em determinados países. Nesse contexto, identificamos a necessidade de rever as recomendações anteriores sobre o manejo dos pacientes brasileiros com DMD. Nosso objetivo principal foi elaborar uma atualização baseada em evidências sobre esses tópicos do consenso.

Searching for new antifungals for the treatment of cryptococcosis

ABSTRACT There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and "bypass" the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available. In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.

Moderate Toxicity of Potential Boron-containing Therapeutic, Dipotassium-trioxohydroxytetrafl uorotriborate - K2 (B3 O3 F4 OH) in Rats and Mice

Abstract Biological activity of boron-containing compounds (BCCs) has been well-known. Growing interest and numerous applications for BCCs have been reported. Boron and boron-containing acids show low acute toxicity in mammals but data on halogenated boroxine (HB) - dipotassium-trioxohydroxytetrafluorotriborate, K2(B3O3F4OH) acute toxicity have not been reported before. This compound, characterized as a potential therapeutic for skin changes, exhibits no observable genotoxicity in doses lower that 0.1 mg/ml in vitro and 55 mg/kg in vivo. It has also been confirmed as an antitumour agent both in vitro and in vivo as well as an inhibitor of enzymes involved in antioxidant mechanisms. The aim of this study was to assess the acute toxicity of HB and to determine the maximum tolerated dose as well as a dose free of any signs of toxicity in different test organisms. Acute toxicity of HB was tested in Sprague-Dawley and Wistar rats and BALB/c mice after single parenteral application of different doses. We determined doses free of any sign of toxicity and LD50 after single dose administration. LD50 of HB ranges from 63 to 75 mg/kg in different test models, meaning that HB shows moderate toxicity

Advantage and progress of model-induced drug development in traditional Chinese medicine / 中国药房

Model-induced drug development （MIDD） is a mathematical and statistical method for constructing， validating and utilizing disease model， drug exposure-response model and pharmaceutical model to promote drug development. With the development of pharmaceutical technology， MIDD is widely used in the field of traditional Chinese medicine and has high practical value. This article summarizes the relevant literature at home and abroad， and finds that MIDD has the advantages of improving the research and development efficiency of traditional Chinese medicine， quickly identifying the applicable population of traditional Chinese medicine， predicting the interaction of drugs， and optimizing the dosage. MIDD has been applied in the studies of effective components of traditional Chinese medicine， quantitative design of prescription， dosage form and preparation process， pilot scale- up， quality and safety， regulatory decision-making and evaluation， etc.

Advances and applications of quantitative systems pharmacology modeling and virtual clinical trials in modern drug development / 药学学报

Quantitative systems pharmacology (QSP) modeling is an emerging computational medicine approach with growing applications and significance in modern drug development. QSP models are generally formulated based on multiscale disease mechanisms and drug-target interactions, which makes them capable of integrating multimodal data from the preclinical and clinical space. This also enables them to generate quantitative characterization of the dynamic disease progression as well as high-throughput predictions of drug-induced efficacy and toxicity signals. Therefore, QSP modeling and model-based virtual clinical trials have been widely implemented to guide drug development, in scenarios such as target identification and assessment, clinical trial design, evaluation of combination therapy and biomarkers, and personalized medicine. In US and Europe, QSP modeling has been developing rapidly in the past 10 years and is now an integral part of the model-informed drug development paradigm; however, in China it is still a nascent field. Here we will present a comprehensive review of the recent advancements of QSP and its impact in modern drug development through a number of case studies. This review will provide guidance for the future drug development efforts and the growth of QSP practice in China.

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC50: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC50: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

Bioactive peptides from scorpion venoms: therapeutic scaffolds and pharmacological tools / 中国天然药物

Evolution and natural selection have endowed animal venoms, including scorpion venoms, with a wide range of pharmacological properties. Consequently, scorpions, their venoms, and/or their body parts have been used since time immemorial in traditional medicines, especially in Africa and Asia. With respect to their pharmacological potential, bioactive peptides from scorpion venoms have become an important source of scientific research. With the rapid increase in the characterization of various components from scorpion venoms, a large number of peptides are identified with an aim of combating a myriad of emerging global health problems. Moreover, some scorpion venom-derived peptides have been established as potential scaffolds helpful for drug development. In this review, we summarize the promising scorpion venoms-derived peptides as drug candidates. Accordingly, we highlight the data and knowledge needed for continuous characterization and development of additional natural peptides from scorpion venoms, as potential drugs that can treat related diseases.

Cases studies of application of model-in-formed drug development in early phase clini-cal trials / 中国药理学与毒理学杂志

Model-informed drug develop-ment(MIDD)is the application of a various math-ematical,statistical,and biological models to facilitate drug development,decision making and regulatory review.As a quantitative tool,MIDD approaches allow an integration of information obtained from non-clinical studies and clinical trials in a drug development program.General understandings of the underlying biology,patho-physiology,and pharmacology can also be incor-porated into the model.MIDD is centered on knowledge and inferences generated from inte-grated models of the physicochemical character-istics of a molecule,its disposition in the body,and its mechanism of action,and how the drug might affect a disease from both an efficacy and a safety perspective.MIDD approaches have the potential to significantly streamline drug develop-ment,by improving clinical trial efficiency,opti-mizing dose and regimen and waive unneces-sary clinical studies.This presentation will use cases studies to demonstrate how to apply MIDD in early phase of clinical trials.

Progress in Establishment and Application of Laboratory Animal Models Related to Development of Male Infertility Drugs / 实验动物与比较医学

As the incidence of male infertility has been increasing during recent years, it is urgent to reveal the pathogenesis of male infertility, as well as to develop the new drugs for treatment of male infertility, in order to solve the declining birth rate and aging problems. The construction and application of male infertile animal models is critical for drug development, which plays an important role in accurately evaluating the efficacy and mechanism of infertility treatment. A suitable infertility model not only can reduce the repeated drug efficacy evaluations, reduce animal usage and the cost of new drug development, but also has important reference value for subsequent clinical trial research. Male infertility laboratory animal models can be constructed through chemical, physical, endocrine, environmental estrogen, gene modification, and immune methods. This article mainly introduces the existing male infertility animal models available for drug development, and briefly introduces the application progress of each model to provide reference for the male infertility drug researchers.

Application of quantitative pharmacology in vaccine research and development: overview and prospect / 中国临床药理学与治疗学

This article introduces the mechanism including antigen presentation, adjuvant, lymphatic system and the characteristics of vaccine, and then summarizes the key applications of core pharmacometrics approaches including QSP, PK/PD, dose response analysis, MBMA, in dose-response, preclinical and clinical translation, and correlation between biomarkers and efficacy of vaccines. It is expected that the successful application of model informed drug development can promote model informed vaccine development so that pharmacometrics makes its due contributions to the development of safer, more effective and more controllable vaccine products.

Research progress in tigliane-type macrocyclic diterpenoids / 中国中药杂志

Tigliane type macrocyclic diterpenoids with special structures and diverse bioactivities are mainly extracted from plants of Euphorbiaceae and Thymelaeaceae. According to the different functional groups, they can be classified into types of phorbol esters, C-4 deoxyphorbol esters, C-12 deoxyphorbol esters, C-16 or C-17 substituted phorbol esters and others. Most of them present promising antiviral activities and cytotoxic activities and are expected to be developed as candidates for anti-AIDS, anti-tuberculosis, and anti-tumor clinical trials, demonstrating great potential for the application in healthcare. This paper reviews 115 novel tigliane-type diterpenoids discovered since 2013 and summarize their chemical structures and bioactivities, aiming to lay a foundation for further development and utilization of these compounds and provide new ideas for the development of clinical drugs.

Artificial intelligence-based drug development: current progress and future challenges / 中国药科大学学报

@#In recent years, artificial intelligence (AI) has been widely applied in the field of drug discovery and development.In particular, natural language processing technology has been significantly improved after the emergence of the pre-training model.On this basis, the introduction of graph neural network has also made drug development more accurate and efficient.In order to help drug developers more systematically and comprehensively understand the application of artificial intelligence in drug discovery, this article introduces cutting-edge algorithms in AI, and elaborates on the various applications of AI in drug development, including drug small molecule design, virtual screening, drug repurposing, and drug property prediction, finally discusses the opportunities and challenges of AI in future drug development.