Clinical Pharmacology & Therapeutics最新文献

{"title":"Drug Interactions Brewing.","authors":"Matthijs W van Hoogdalem, Kathleen M Giacomini","doi":"10.1002/cpt.3709","DOIUrl":"https://doi.org/10.1002/cpt.3709","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101271","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":"Dose Optimization in Oncology Drug Development: Risk Factors for Postmarketing Requirements and Commitments.","authors":"Hiroe Kitagaki, Kentaro Takeda, Kazuya Murai, Hideki Maeda","doi":"10.1002/cpt.3722","DOIUrl":"https://doi.org/10.1002/cpt.3722","url":null,"abstract":"<p><p>Optimal dosing of oncological drugs is historically determined based on the \"higher is better\" paradigm. However, a paradigm shift in optimal dose selection has occurred in the development of new modalities, including molecularly targeted drugs, antibody drugs, and immunotherapies. In 2021, Project Optimus was launched by the Food and Drug Administration Oncology Center of Excellence to reform the dose optimization and dose selection paradigm in oncology drug development. In August 2024, \"Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases\" was published, encouraging randomized evaluation of the benefit/risk profile of a range of doses before initiating a registration trial. Although Project Optimus offers general guidance on dose optimization, it does not specify which early clinical data requires a more cautious approach to dose optimization. This is the first comprehensive study to investigate newly approved oncology drugs by the FDA over a long period and to identify the risk factors for postmarketing requirement or commitment to dose optimization, using logistic regression analysis. Our findings show that when the labeled dose is the maximum tolerated dose, the percentage of adverse reactions leading to treatment discontinuation is increased, and an exposure-safety relationship is established, the risk for postmarketing requirement or commitment to dose optimization is increased. Our study will provide actionable, data-driven insights into dose optimization strategies by objectively and quantitatively evaluating risk factors. These findings will serve as valuable guidance for designing more effective early-phase trials, complementing the FDA Project Optimus guidance.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109267","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":"In this Issue.","authors":"Alethea Gerding","doi":"10.1002/cpt.3710","DOIUrl":"https://doi.org/10.1002/cpt.3710","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101273","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":"Evaluating the Evidence for CYP2C19 Inhibitor Classifications: A Scoping Review.","authors":"Jean G Malavé, Andrés Lopez, Thi Doan, Emily J Cicali, Zeruesenay Desta, Caitrin W McDonough, Larisa H Cavallari","doi":"10.1002/cpt.3712","DOIUrl":"https://doi.org/10.1002/cpt.3712","url":null,"abstract":"<p><p>The Food and Drug Administration (FDA) Table of Inhibitors and the Flockhart Table™ are important references for identifying CYP2C19 inhibitors. Accurate inhibitor classification is essential for evaluating phenoconversion and managing drug-drug interactions. The objective of this study was to assess the concordance between inhibitor classifications according to the FDA and Flockhart tables and pharmacokinetic data from the primary literature. A scoping review of PubMed, product labels, and the Drug Interactions Database (DIDB®) up to April 2024 was conducted. Inhibitor-substrate pairs (e.g., fluoxetine-omeprazole) were assigned literature-reported classifications (i.e., weak, moderate, or strong) based on pharmacokinetic data. Concordance between literature-reported and listed classifications was evaluated. Of 90 inhibitor-substrate pairs identified, 66% involved sensitive substrates, which were the focus of our primary analysis. Among sensitive inhibitor-substrate pairs, 36% of FDA-listed and 45% of Flockhart-listed classifications were concordant with the literature. CYP2C19 phenotype appeared to impact concordance, with greater concordance among normal metabolizers for both FDA-listed (42%) and Flockhart-listed (50%) classifications. Steady state status and dosing also appeared to affect concordance. Discrepancies between listed and literature-reported classifications led to the following recommendations: (1) upgrade fluoxetine from moderate to strong in the Flockhart Table™, (2) upgrade fluconazole from moderate to strong in the Flockhart Table™, (3) downgrade omeprazole (and esomeprazole) from moderate to weak in the Flockhart Table™, and (4) include footnotes describing dose-dependent inhibition for fluvoxamine and fluconazole in both tables. These recommendations aim to improve the accuracy of CYP2C19 inhibitor classifications and the clinical utility of these tables.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101272","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":"Standing on the Shoulders of Giants: 125th Anniversary of the American Society for Clinical Pharmacology & Therapeutics","authors":"Piet H. van der Graaf,&nbsp;Alethea B. Gerding","doi":"10.1002/cpt.3666","DOIUrl":"https://doi.org/10.1002/cpt.3666","url":null,"abstract":"&lt;p&gt;How does the flagship journal of a scientific society contribute to celebrating said society's birthday? This question was discussed for the first time a year ago by the editorial team of &lt;i&gt;Clinical Pharmacology &amp; Therapeutics&lt;/i&gt; (&lt;i&gt;CPT&lt;/i&gt;) in anticipation of the 2025 American Society for Clinical Pharmacology &amp; Therapeutics (ASCPT) Annual Meeting, which will mark its 125th anniversary.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; We decided to mark this milestone with a special themed issue of &lt;i&gt;CPT&lt;/i&gt;, encapsulating the evolution of clinical pharmacology and its critical role in translating scientific innovations to novel therapies (Figure 1). Of course, we could have done this in various ways, but we settled on the idea to reprint the most highly cited original research article from each decade since the launch of &lt;i&gt;CPT&lt;/i&gt; ~ 60 years ago, each with an accompanying Commentary on the importance of the work (Table 1). We believe the result is a unique whistle-stop tour of landmark papers that have defined our discipline and are the foundation for where it is today. As a reviewer noted of one of the commentary/historical article pairs, “I think that every PharmD and graduate student in the pharmacy school should have this commentary on their reading list.”&lt;/p&gt;&lt;p&gt;It starts with one of the first clinical studies of ketamine six decades ago&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; and the classic work by Sheiner &lt;i&gt;et al&lt;/i&gt;.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;, which became the foundation of what is now known as pharmacometrics and model-informed drug development (MIDD) in the 1970s.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Next, our overview highlights the seminal work that helped to define the critical role of transporters in the 1990's,&lt;span&gt;&lt;sup&gt;7-10&lt;/sup&gt;&lt;/span&gt; and subsequently the first papers on the clinical pharmacology of novel targeted cancer therapies at the beginning of this century.&lt;span&gt;&lt;sup&gt;11, 12&lt;/sup&gt;&lt;/span&gt; Perhaps unsurprisingly, the paper that defined the current decade—based on our criteria of highest number of citations—was related to the role of clinical pharmacology in the COVID pandemic.&lt;span&gt;&lt;sup&gt;13, 14&lt;/sup&gt;&lt;/span&gt; The paper “A method for estimating the probability of adverse drug reactions” by Naranjo &lt;i&gt;et al&lt;/i&gt;.,&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; which represents the 1980s decade, deserves a special mention since it is the most highly-cited &lt;i&gt;CPT&lt;/i&gt; paper of all time. We were honored that two co-authors of the original work, Drs Greenblatt and Sellers, were willing to share their personal reflections on their seminal article.&lt;span&gt;&lt;sup&gt;16&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Selecting only seven papers does not do justice to the many other great works &lt;i&gt;CPT&lt;/i&gt; has published over the decades, and restricting our selected articles to original research further narrowed our scope. Therefore, we have created a special virtual issue that includes the 15 most-cited articles from each decade. You can find this at &lt;i&gt;CPT&lt;/i&gt;'s homepage (https://ascpt.onlinelibrary.wiley.com/journal/153","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 6","pages":"1481-1484"},"PeriodicalIF":6.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3666","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091258","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}

{"title":"Deciphering the Relative Contribution of CYP3A4 Versus P-Glycoprotein for the Shared Substrate Cyclosporine—Commentary on Lown et al.","authors":"Ingolf Cascorbi,&nbsp;Richard B. Kim","doi":"10.1002/cpt.3619","DOIUrl":"https://doi.org/10.1002/cpt.3619","url":null,"abstract":"<p>The oral bioavailability of cyclosporine, a substrate of both CYP3A4 and P-glycoprotein, is subject to large inter-individual variability, which requires frequent monitoring of plasma concentrations. In 1997, the study by Lown <i>et al</i>. showed that—in addition to hepatic CYP3A4—the expression of P-gp in the intestine significantly influences the pharmacokinetics of cyclosporine in kidney transplant patients. The results contributed considerably to a better understanding of the function of the intestinal P-glycoprotein for drug clearance.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 6","pages":"1546-1561"},"PeriodicalIF":6.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3619","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091560","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}

{"title":"A Reflection on the Evolution of Antibody-Based Therapies in Oncology: Trastuzumab as an Exemplar—Commentary on Dijkers et al.","authors":"Sarah A. Holstein","doi":"10.1002/cpt.3651","DOIUrl":"https://doi.org/10.1002/cpt.3651","url":null,"abstract":"&lt;p&gt;The year 2025 marks the 50th anniversary of Köhler and Milstein's publication reporting the generation of hybridoma cell lines capable of producing mAb.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Not only has this discovery enabled scientific progress across the spectrum of biomedical research, but the impact on clinical pharmacology and therapeutics has been remarkable. In 1980, Nadler et al. published a case report detailing the transient activity of a murine mAb targeting a lymphoma-associated antigen.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Antibody-based therapies have subsequently evolved from murine mAbs to chimeric mAbs to humanized mAbs to fully human mAbs, radiolabeled antibodies, antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs) and bispecific antibodies (BsAbs), amongst others. While many of the mAbs have targeted tumor-specific antigens, others have been more directly immunomodulatory in nature (e.g., checkpoint inhibitors), yielding impressive results in previously difficult-to-treat malignancies (e.g., melanoma, renal cell carcinoma). A 2022 publication reported that the Umabs Antibody Therapies Database listed 162 antibody therapies that had been approved by at least one regulatory agency (not including biosimilar, diagnostic and veterinary antibodies).&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; These 162 antibody therapies encompassed 91 drug targets and included 115 canonical antibodies, 14 ADCs, 7 BsAbs, 8 antibody fragments, 3 radiolabeled antibodies, 1 antibody-conjugate immunotoxin, 2 immunoconjugates, and 12 Fc-Fusion proteins.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The field of cancer has been most prominently impacted by the development of mAb-based therapies, with 66 antibody therapeutics granted a first approval for a cancer indication in the United States or the European Union between 1997 and 2024.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Not included in these totals are therapies such as chimeric antigen receptor (CAR) T-cell products which include an antibody fragment in the CAR construct. &lt;b&gt;Figure&lt;/b&gt; 1 highlights some of the major events over the past 50 years that have transformed the cancer therapeutic landscape from an antibody-based perspective.&lt;/p&gt;&lt;p&gt;The first humanized mAb to receive FDA approval for a solid tumor indication was trastuzumab in 1998. Trastuzumab targets the extracellular domain of human epidermal growth factor receptor 2 protein (HER-2) and is thought to induce cell death through multiple mechanisms of action, including attenuation of signal transduction pathways downstream of HER2, induction of antibody-dependent cellular cytotoxicity (ADCC) and prevention of HER2 shedding. Trastuzumab was first approved for the treatment of HER2-positive metastatic breast cancer and then later approved in the adjuvant setting. There has subsequently been a slew of HER2-targeting antibody-based therapies approved for the treatment of HER2-positive breast cancer, including another mAb (pertuzumab, which binds to a different extracellular domain of HER2, blocking liga","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 6","pages":"1577-1587"},"PeriodicalIF":6.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3651","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091557","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}

{"title":"Trust, Transparency, and Translation: How Clinical Pharmacologists Can Strengthen Public Confidence in Pandemic Responses—Commentary on Schmith et al.","authors":"Brian W. Corrigan","doi":"10.1002/cpt.3670","DOIUrl":"https://doi.org/10.1002/cpt.3670","url":null,"abstract":"<p>On April 3, 2020, data were published showing <i>in vitro</i> efficacy of ivermectin against COVID-19. By April 26, 2020, Schmith <i>et al</i>. published that even at supratherapeutic doses, ivermectin was unlikely to reach target IC90 concentrations <i>in vivo</i>. Nevertheless, many countries adopted ivermectin, and millions of patients received treatment even after definitive evidence of ineffectiveness became available. The ivermectin debate catalyzed public mistrust in science and health authorities and has consequences for future pandemic preparedness.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 6","pages":"1588-1595"},"PeriodicalIF":6.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091558","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":"In the Cradle of Pharmacometric Methodology: Introducing Population PKPD Modeling, Simultaneous Analysis, and the Effect-Compartment Model—Commentary on Sheiner et al.","authors":"Mats O. Karlsson","doi":"10.1002/cpt.3663","DOIUrl":"https://doi.org/10.1002/cpt.3663","url":null,"abstract":"<p>In the decades preceding 1970s, there were considerable advances in theoretical descriptions of pharmacokinetics, drug action, and the time-course of dose-concentration-response relations. However, delayed drug effects and how to analyze data across individuals still offered a considerable challenge. Sheiner et al., through the formulation of the effect-compartment model, the utilization of nonlinear mixed effects models, and simultaneous PKPD analysis, offered solutions to these issues that still today are considered state-of-the-art.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 6","pages":"1516-1532"},"PeriodicalIF":6.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144091559","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}

{"title":"FDA Adverse Event Reporting System (FAERS) Essentials: A Guide to Understanding, Applying, and Interpreting Adverse Event Data Reported to FAERS.","authors":"Emeri Potter, Melissa Reyes, Jennifer Naples, Gerald Dal Pan","doi":"10.1002/cpt.3701","DOIUrl":"https://doi.org/10.1002/cpt.3701","url":null,"abstract":"<p><p>The US Food and Drug Administration (FDA) performs safety assessments throughout the life cycle of a drug. Postmarketing safety surveillance promotes the identification of adverse events not known at the time of approval. Adverse event reports, also called individual case safety reports (ICSRs), submitted to FDA, are collected and stored in the FDA Adverse Event Reporting System (FAERS). ICSRs stored in FAERS may be reviewed-along with multiple other data sources-to detect potential safety signals and to perform a thorough evaluation to determine if a causal association exists between a drug and an adverse event. Although FAERS is a powerful tool for drug safety surveillance and assessment, understanding the content, application, and proper interpretation of the data contained in FAERS is necessary to reach scientifically and medically accurate conclusions and contextualize findings. This article aims to highlight considerations and explain fundamental concepts of FAERS to promote accurate analyses and appropriate interpretation of the data available.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092286","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}