Jaime Algorta, Stella Kepha, Alejandro Krolewiecki, Hanbin Li, Justin Giang, Pedro Fleitas, Charles Mwandawiro, José Muñoz
Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixed-dose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure-response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T. trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure-response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a two-compartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure-response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T. trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.
毛滴虫是一种通过土壤传播的蠕虫，可引起肠道疾病。阿苯达唑是标准的治疗方法，尽管其疗效一般，但与伊维菌素合用可提高疗效。固定剂量复方制剂主要在大规模用药方面更具实用优势。本文旨在确定创新型阿苯达唑/伊维菌素复方制剂的群体药代动力学模型和暴露-反应。数据来源于一项针对健康成人的 I 期临床试验和一项针对感染滴虫的儿童和青少年的 II 期试验。使用 NONMEM® 为阿苯达唑和伊维菌素建立了非线性混合效应模型。使用每个个体的药代动力学参数的经验贝叶斯估计值计算曲线下面积，并用于评估治愈率和药代动力学暴露量之间的暴露-反应。阿苯达唑的药代动力学采用一阶吸收的二室模型进行描述，伊维菌素的药代动力学采用先零阶后一阶吸收的二室模型进行描述。阿苯达唑和伊维菌素的清除率和分布容积均随体重增加而增加。使用联合疗法治疗的儿童和青少年体内阿苯达唑和伊维菌素的第一天曲线下面积与使用对照药物治疗的健康成人相似。在治愈率和药物暴露量之间观察到一种平坦的暴露量-反应关系。该研究描述了阿苯达唑和伊维菌素复方制剂在儿童、青少年和成人（健康或感染了毛滴虫）中的群体药代动力学。在 II 期试验中选择的剂量适合随后的 III 期试验。
{"title":"Population Pharmacokinetics and Exposure-Response Analysis of a Fixed-Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults.","authors":"Jaime Algorta, Stella Kepha, Alejandro Krolewiecki, Hanbin Li, Justin Giang, Pedro Fleitas, Charles Mwandawiro, José Muñoz","doi":"10.1002/cpt.3424","DOIUrl":"https://doi.org/10.1002/cpt.3424","url":null,"abstract":"<p><p>Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixed-dose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure-response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T. trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure-response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a two-compartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure-response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T. trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gauri G Rao, Quentin Vallé, Ramya Mahadevan, Rajnikant Sharma, Jeremy J Barr, Daria Van Tyne
Effectively treating multidrug-resistant bacterial infections remains challenging due to the limited drug development pipeline and a scarcity of novel agents effective against these highly resistant pathogens. Bacteriophages (phages) are a potential addition to the antimicrobial treatment arsenal. Though, phages are currently being tested in clinical trials for antibiotic-resistant infections, phages lack a fundamental understanding of optimal dosing in humans. Rationally designed preclinical studies using in vitro and in vivo infection models, allow us to assess clinically relevant phage +/- antibiotic exposure (pharmacokinetics), the resulting treatment impact on the infecting pathogen (pharmacodynamics) and host immune response (immunodynamics). A mechanistic modeling framework allows us to integrate this knowledge gained from preclinical studies to develop predictive models. We reviewed recently published mathematical models based on in vitro and/or in vivo data that evaluate the effects of varying bacterial or phage densities, phage characteristics (burst size, adsorption rate), phage pharmacokinetics, phage-antibiotic combinations and host immune responses. In our review, we analyzed study designs and the data used to inform the development of these mechanistic models. Insights gained from model-based simulations were reviewed as they help identify crucial phage parameters for determining effective phage dosing. These efforts contribute to bridging the gap between phage therapy research and its clinical translation.
{"title":"Crossing the Chasm: How to Approach Translational Pharmacokinetic-Pharmacodynamic Modeling of Phage Dosing.","authors":"Gauri G Rao, Quentin Vallé, Ramya Mahadevan, Rajnikant Sharma, Jeremy J Barr, Daria Van Tyne","doi":"10.1002/cpt.3426","DOIUrl":"https://doi.org/10.1002/cpt.3426","url":null,"abstract":"<p><p>Effectively treating multidrug-resistant bacterial infections remains challenging due to the limited drug development pipeline and a scarcity of novel agents effective against these highly resistant pathogens. Bacteriophages (phages) are a potential addition to the antimicrobial treatment arsenal. Though, phages are currently being tested in clinical trials for antibiotic-resistant infections, phages lack a fundamental understanding of optimal dosing in humans. Rationally designed preclinical studies using in vitro and in vivo infection models, allow us to assess clinically relevant phage +/- antibiotic exposure (pharmacokinetics), the resulting treatment impact on the infecting pathogen (pharmacodynamics) and host immune response (immunodynamics). A mechanistic modeling framework allows us to integrate this knowledge gained from preclinical studies to develop predictive models. We reviewed recently published mathematical models based on in vitro and/or in vivo data that evaluate the effects of varying bacterial or phage densities, phage characteristics (burst size, adsorption rate), phage pharmacokinetics, phage-antibiotic combinations and host immune responses. In our review, we analyzed study designs and the data used to inform the development of these mechanistic models. Insights gained from model-based simulations were reviewed as they help identify crucial phage parameters for determining effective phage dosing. These efforts contribute to bridging the gap between phage therapy research and its clinical translation.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.
靶向肿瘤抗原和 T 细胞的 T 细胞靶向双特异性抗体 (TCE) 在治疗癌症，尤其是血液病适应症方面大有可为。双特异性抗体的临床开发通常需要经过漫长的首次人体试验（FIH）和多次剂量递增试验，最终获得早期概念验证（POC），从而决定是否进行进一步的临床开发或选择剂量。与靶点、产品、疾病和患者群体有关的多种因素会影响 TCE 的疗效和安全性。复杂的作用机制限制了临床前模型向临床的转化，从而为简化临床开发带来了挑战。此外，与传统化疗不同，TCEs 在临床中的最高剂量和二期推荐剂量（RP2D）往往不是以最大耐受剂量（MTD）为指导，而是基于对获益/风险概况的综合剂量-反应评估。这些不确定性给转化和临床药理学家（PK/PD 科学家）以及临床医生带来了复杂的挑战，如何才能设计出高效的临床研究来指导研发工作？为此，该领域的专家们在美国医药科学家协会的支持下，回顾了从已发表的文献和目前上市的产品中学到的知识，分享了对 FIH 和临床药理策略的看法，以支持 TCE 的早期临床开发。
{"title":"Industry Perspective on First-in-Human and Clinical Pharmacology Strategies to Support Clinical Development of T-Cell Engaging Bispecific Antibodies for Cancer Therapy.","authors":"Prathap Nagaraja Shastri,Nirav Shah,Martin Lechmann,Hardik Mody,Marc W Retter,Min Zhu,Tommy Li,Jun Wang,Naveed Shaik,Xirong Zheng,Meric Ovacik,Fei Hua,Vibha Jawa,Christophe Boetsch,Yanguang Cao,John Burke,Kaushik Datta,Kapil Gadkar,Vijay Upreti,Alison Betts","doi":"10.1002/cpt.3439","DOIUrl":"https://doi.org/10.1002/cpt.3439","url":null,"abstract":"T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Clinical pharmacology is a discipline that includes education, research, and the implementation of knowledge into clinical practice, which ranges from precision dosing to therapeutic drug monitoring, and most recently, to the implementation of pharmacogenetic/pharmacogenomic (PGx) testing services to precisely administer drugs based on an individual's genetic make-up. In fact, PGx has become one of the core scientific pillars of the American Society for Clinical Pharmacology and Therapeutics (<i>ASCPT</i>) and its flagship journal, Clinical Pharmacology & Therapeutics (<i>CPT</i>). PGx implementation services have been rapidly adopted in academic healthcare centers throughout the United States and in Europe. These services are grounded in the availability of new genetic technologies and a wealth of scientific discoveries, generally describing the influence of genetic variants on drug responses in European ancestral populations. With the availability of PGx information, the Clinical Pharmacogenetics Implementation Consortium (<i>CPIC</i>) was established to develop guidelines on drug and dose selection for individuals based on their genetic information.<span><sup>1</sup></span> These guidelines, published in <i>CPT</i>,<span><sup>2, 3</sup></span> are increasingly being incorporated into clinical decision support systems, and used to advise providers on how to use PGx information in drug or dose selection.<span><sup>1</sup></span> However, despite of their widespread adoption in academic medical centers, there remains a resistance to PGx testing among healthcare providers. This can be attributed to various factors, such as cost of testing, requirements for expensive infrastructure, lack of provider education, and skepticism that there is any major benefit of testing.<span><sup>4</sup></span> </p><p>With the goal of stimulating discussion among clinical pharmacologists and others, the editors of <i>CPT</i> sponsored a session at the 2024 annual meeting of <i>ASCPT</i>, entitled: “Is pharmacogenetic testing a vital tool for enhancing therapeutic management of patients worldwide?” (Colorado Springs CO, March 28, 2024). The session, which was moderated by <i>CPT</i> Editor-in-Chief, Piet van der Graaf, and Deputy Editor, Kathleen Giacomini, included four clinical pharmacologists or geneticists who brought different types of expertise to the panel discussion: Karen E. Brown, PharmD (University of Montana), David J. Greenblatt, MD (Tufts University School of Medicine), Henk-Jan Guchelaar, PharmD PhD (Leiden University Medical Center), and Neal Hanchard, MD PhD (National Institute of Health). To spark audience engagement, the moderators designed a survey (<b>Supplementary Materials</b> <b>S1</b> )—distributed to the membership of the ASCPT a month before the annual meeting—with the aim to gain insight into the attitudes of clinical pharmacologists towards PGx testing.</p><p>The results of the survey, with
{"title":"Is Pharmacogenetic Testing a Vital Tool for Enhancing Therapeutic Management of Patients Worldwide?","authors":"Kathleen M. Giacomini, Piet H. van der Graaf","doi":"10.1002/cpt.3404","DOIUrl":"https://doi.org/10.1002/cpt.3404","url":null,"abstract":"<p>Clinical pharmacology is a discipline that includes education, research, and the implementation of knowledge into clinical practice, which ranges from precision dosing to therapeutic drug monitoring, and most recently, to the implementation of pharmacogenetic/pharmacogenomic (PGx) testing services to precisely administer drugs based on an individual's genetic make-up. In fact, PGx has become one of the core scientific pillars of the American Society for Clinical Pharmacology and Therapeutics (<i>ASCPT</i>) and its flagship journal, Clinical Pharmacology & Therapeutics (<i>CPT</i>). PGx implementation services have been rapidly adopted in academic healthcare centers throughout the United States and in Europe. These services are grounded in the availability of new genetic technologies and a wealth of scientific discoveries, generally describing the influence of genetic variants on drug responses in European ancestral populations. With the availability of PGx information, the Clinical Pharmacogenetics Implementation Consortium (<i>CPIC</i>) was established to develop guidelines on drug and dose selection for individuals based on their genetic information.<span><sup>1</sup></span> These guidelines, published in <i>CPT</i>,<span><sup>2, 3</sup></span> are increasingly being incorporated into clinical decision support systems, and used to advise providers on how to use PGx information in drug or dose selection.<span><sup>1</sup></span> However, despite of their widespread adoption in academic medical centers, there remains a resistance to PGx testing among healthcare providers. This can be attributed to various factors, such as cost of testing, requirements for expensive infrastructure, lack of provider education, and skepticism that there is any major benefit of testing.<span><sup>4</sup></span>\u0000 </p><p>With the goal of stimulating discussion among clinical pharmacologists and others, the editors of <i>CPT</i> sponsored a session at the 2024 annual meeting of <i>ASCPT</i>, entitled: “Is pharmacogenetic testing a vital tool for enhancing therapeutic management of patients worldwide?” (Colorado Springs CO, March 28, 2024). The session, which was moderated by <i>CPT</i> Editor-in-Chief, Piet van der Graaf, and Deputy Editor, Kathleen Giacomini, included four clinical pharmacologists or geneticists who brought different types of expertise to the panel discussion: Karen E. Brown, PharmD (University of Montana), David J. Greenblatt, MD (Tufts University School of Medicine), Henk-Jan Guchelaar, PharmD PhD (Leiden University Medical Center), and Neal Hanchard, MD PhD (National Institute of Health). To spark audience engagement, the moderators designed a survey (<b>Supplementary Materials</b> \u0000 <b>S1</b>\u0000 )—distributed to the membership of the ASCPT a month before the annual meeting—with the aim to gain insight into the attitudes of clinical pharmacologists towards PGx testing.</p><p>The results of the survey, with","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"116 4","pages":"885-889"},"PeriodicalIF":6.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Regulators increasingly rely on real-world evidence generated from routine-care health data to evaluate novel therapies. Particularly, external control arms are increasingly used to supplement and contextualize efficacy and safety claims of single arm clinical trials for rare disease therapies. However, there are a number of methodological issues that may affect the validity of results derived from such comparisons. In this mini-review, we briefly summarize frequently used approaches and outline some of the most important criticisms and paths forward.
{"title":"External Controls to Study Treatment Effects in Rare Diseases: Challenges and Future Directions","authors":"Janick Weberpals, Shirley V. Wang","doi":"10.1002/cpt.3443","DOIUrl":"10.1002/cpt.3443","url":null,"abstract":"<p>Regulators increasingly rely on real-world evidence generated from routine-care health data to evaluate novel therapies. Particularly, external control arms are increasingly used to supplement and contextualize efficacy and safety claims of single arm clinical trials for rare disease therapies. However, there are a number of methodological issues that may affect the validity of results derived from such comparisons. In this mini-review, we briefly summarize frequently used approaches and outline some of the most important criticisms and paths forward.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"116 6","pages":"1521-1524"},"PeriodicalIF":6.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"What Is Rare and What Is Orphan? A Guide to the Regulatory Terminology","authors":"Kristina Larsson","doi":"10.1002/cpt.3446","DOIUrl":"10.1002/cpt.3446","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"116 6","pages":"1395-1397"},"PeriodicalIF":6.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Di Zhou, Roman Kischel, Sabine Stienen, Danielle Townsley, Alexander Sternjak, Michael Lutteropp, Julie Bailis, Matthias Friedrich, Benno Rattel, Khamir Mehta, Vijay V. Upreti
Bispecific T‐cell engagers (Bi‐TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best‐in‐class therapeutics for cancer. However, defining the dose and dosing regimen for the first‐in‐human (FIH) studies of Bi‐TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub‐therapeutic dosing. Leveraging our in‐depth and broad clinical development experience across three generations of Bi‐TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half‐life extended (HLE) Bi‐TCE for gastric cancer. This modified MABEL approach enabled a 10‐fold higher starting dose that was deemed safe and well tolerated and saved at least two dose‐escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi‐TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi‐TCEs.
{"title":"An Innovative Approach to Optimize First‐In‐Human Minimal Anticipated Biological Effect Level Based Starting Dose in Oncology Trials for Bispecific T‐Cell Engagers: Experience from A Solid Tumor Bispecific T‐Cell Engager","authors":"Di Zhou, Roman Kischel, Sabine Stienen, Danielle Townsley, Alexander Sternjak, Michael Lutteropp, Julie Bailis, Matthias Friedrich, Benno Rattel, Khamir Mehta, Vijay V. Upreti","doi":"10.1002/cpt.3431","DOIUrl":"https://doi.org/10.1002/cpt.3431","url":null,"abstract":"Bispecific T‐cell engagers (Bi‐TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best‐in‐class therapeutics for cancer. However, defining the dose and dosing regimen for the first‐in‐human (FIH) studies of Bi‐TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub‐therapeutic dosing. Leveraging our in‐depth and broad clinical development experience across three generations of Bi‐TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, <jats:italic>in vitro</jats:italic>, <jats:italic>in vivo</jats:italic> pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half‐life extended (HLE) Bi‐TCE for gastric cancer. This modified MABEL approach enabled a 10‐fold higher starting dose that was deemed safe and well tolerated and saved at least two dose‐escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi‐TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi‐TCEs.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"195 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thanh Phuong Pham Nguyen, Charles E. Leonard, Colleen M. Brensinger, Warren B. Bilker, Sophie P. Chung, John R. Horn, Kacie Bogar, Todd A. Miano, Sean Hennessy
In a prior screening study, saxagliptin, a dipeptidyl peptidase‐4 inhibitor (DPP‐4i), was found to have an increased rate of serious bleeding when used concomitantly with several oral anticoagulants (OACs). We aimed to confirm or refute the associations between concomitant use of individual OACs and DPP‐4is and serious bleeding in a large US database, using self‐controlled case series (SCCS) and case‐crossover (CCO) designs. The study population was eligible Medicare beneficiaries co‐exposed to a DPP‐4i (precipitant) and either an OAC (object drug) or lisinopril (negative control object drug) in 2016–2020. For the SCCS, we used conditional Poisson regression to estimate adjusted rate ratios (RRs) between each co‐exposure (vs. not) and serious bleeding and divided the RR by the adjusted RR for the corresponding lisinopril + precipitant pair to obtain ratios of RRs (RRRs). For the CCO, we estimated the adjusted odds ratios (ORs) of exposure to the precipitant in the focal window vs. referent window using multivariable conditional logistic regression and divided the ORs in the object drug‐exposed cases over the ORs in negative object drug‐exposed cases to obtain the ratios of ORs (RORs). The adjusted RRRs for serious bleeding ranged from 0.32 (0.05–1.91) for apixaban/lisinopril + saxagliptin to 3.49 (1.29–9.48) for warfarin/lisinopril + linagliptin. The adjusted RORs ranged from 0.01 (0.00–0.20) for rivaroxaban/lisinopril + saxagliptin to 2.99 (0.74–12.11) for apixaban/lisinopril + linagliptin. While we could not confirm previously identified signals because of statistical imprecision, several numerically elevated estimates still warrant caution in concomitant use and further examination.
{"title":"Concomitant Use of Oral Anticoagulants with Oral Dipeptidyl Peptidase‐4 Inhibitors and Serious Bleeding Events","authors":"Thanh Phuong Pham Nguyen, Charles E. Leonard, Colleen M. Brensinger, Warren B. Bilker, Sophie P. Chung, John R. Horn, Kacie Bogar, Todd A. Miano, Sean Hennessy","doi":"10.1002/cpt.3442","DOIUrl":"https://doi.org/10.1002/cpt.3442","url":null,"abstract":"In a prior screening study, saxagliptin, a dipeptidyl peptidase‐4 inhibitor (DPP‐4i), was found to have an increased rate of serious bleeding when used concomitantly with several oral anticoagulants (OACs). We aimed to confirm or refute the associations between concomitant use of individual OACs and DPP‐4is and serious bleeding in a large US database, using self‐controlled case series (SCCS) and case‐crossover (CCO) designs. The study population was eligible Medicare beneficiaries co‐exposed to a DPP‐4i (precipitant) and either an OAC (object drug) or lisinopril (negative control object drug) in 2016–2020. For the SCCS, we used conditional Poisson regression to estimate adjusted rate ratios (RRs) between each co‐exposure (vs. not) and serious bleeding and divided the RR by the adjusted RR for the corresponding lisinopril + precipitant pair to obtain ratios of RRs (RRRs). For the CCO, we estimated the adjusted odds ratios (ORs) of exposure to the precipitant in the focal window vs. referent window using multivariable conditional logistic regression and divided the ORs in the object drug‐exposed cases over the ORs in negative object drug‐exposed cases to obtain the ratios of ORs (RORs). The adjusted RRRs for serious bleeding ranged from 0.32 (0.05–1.91) for apixaban/lisinopril + saxagliptin to 3.49 (1.29–9.48) for warfarin/lisinopril + linagliptin. The adjusted RORs ranged from 0.01 (0.00–0.20) for rivaroxaban/lisinopril + saxagliptin to 2.99 (0.74–12.11) for apixaban/lisinopril + linagliptin. While we could not confirm previously identified signals because of statistical imprecision, several numerically elevated estimates still warrant caution in concomitant use and further examination.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"50 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The number of drugs developed by non‐global companies, including biotech start‐ups, has increased; however, their characteristics and impact on global regulatory approval are not well understood. Using a public database, we identified new molecular entities (NMEs) approved for hematologic malignancies in the US from January 2011 to December 2022. They were divided into those submitted by non‐global companies (non‐global group) and those by global companies (global group). We identified 48 NMEs, of which 19 (40%) were classified as non‐global. Of these, 13 (68%) were from US‐based companies. In the non‐global group, 63% (12/19) of the NMEs had received accelerated approval in the US, of which only 50% (6/12) had a post‐approval confirmatory trial by September 2023. Regarding the impact on the approval in the European Union (EU) and Japan, the unapproval rate of 2 years after US approval was higher in the non‐global group than in the global group in the EU (56% vs. 21%) and Japan (94% vs. 64%). In conclusion, many NMEs from non‐global companies had received accelerated approval in the US based on phase I/II trials. NMEs from non‐global companies had a higher unapproval rate at 2 years in both the EU and Japan.
{"title":"Characteristics of Drugs from Non‐Global Companies for Hematologic Malignancies and Impact on Global Regulatory Approval","authors":"Kensuke Matsuda, Sumimasa Nagai, Koichi Sugimoto","doi":"10.1002/cpt.3440","DOIUrl":"https://doi.org/10.1002/cpt.3440","url":null,"abstract":"The number of drugs developed by non‐global companies, including biotech start‐ups, has increased; however, their characteristics and impact on global regulatory approval are not well understood. Using a public database, we identified new molecular entities (NMEs) approved for hematologic malignancies in the US from January 2011 to December 2022. They were divided into those submitted by non‐global companies (non‐global group) and those by global companies (global group). We identified 48 NMEs, of which 19 (40%) were classified as non‐global. Of these, 13 (68%) were from US‐based companies. In the non‐global group, 63% (12/19) of the NMEs had received accelerated approval in the US, of which only 50% (6/12) had a post‐approval confirmatory trial by September 2023. Regarding the impact on the approval in the European Union (EU) and Japan, the unapproval rate of 2 years after US approval was higher in the non‐global group than in the global group in the EU (56% vs. 21%) and Japan (94% vs. 64%). In conclusion, many NMEs from non‐global companies had received accelerated approval in the US based on phase I/II trials. NMEs from non‐global companies had a higher unapproval rate at 2 years in both the EU and Japan.","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"26 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142197052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号