Clinical Pharmacology & Therapeutics最新文献

{"title":"Response to FDA Adverse Event Reporting System (FAERS) Essentials: A Reflection on Study Conception","authors":"Melissa Reyes, Emeri Potter, Gerald Dal Pan","doi":"10.1002/cpt.70040","DOIUrl":"10.1002/cpt.70040","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937192","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":"Combined Biologics and Exclusive Enteral Nutrition Promote Early Transmural Healing and Improve Long-Term Outcomes in Crohn's Disease: A Multicenter Retrospective Study.","authors":"Haixia Ren, Jing An, Wei Chen, Jiao Li, Xing Li, Anning Yin, Jing Wang, Wei Wang, Jingyun Cheng, Jian Kang, Yaqing Xu, Yueyue Lu, Juan Su, Qian Zhou, Huipeng Wan, Zimeng Zhang, Ping An","doi":"10.1002/cpt.70034","DOIUrl":"https://doi.org/10.1002/cpt.70034","url":null,"abstract":"<p><p>Transmural healing (TH), a comprehensive therapeutic target in Crohn's disease (CD), is associated with reduced long-term complications. However, evidence on the role of exclusive enteral nutrition (EEN) in TH remains limited. This study aimed to evaluate the efficacy of biologics combined with 16-week EEN in achieving early TH and improving clinical outcomes. This real-world, multicenter retrospective study analyzed medical records of patients with moderate-to-severe CD from 2016 to 2024. Patients received either biologics with concomitant 16-week EEN (BioEEN) or biologics alone (Bio). Clinical and endoscopic outcomes, including transmural healing, were assessed at week 16, year 1, and year 2. At baseline, demographic and clinical characteristics were comparable between the two groups. The BioEEN group demonstrated superior clinical response rates compared to the Bio group (95.1% vs. 70.6% at week 16; P < 0.001), with sustained benefits at week 52 (87.8% vs. 59.5%; P < 0.001). Subgroup analysis revealed higher endoscopic response, mucosal healing, and TH rates in both colorectal and ileal segments at weeks 16 and 52 in the BioEEN group. Additionally, the BioEEN group had significantly lower rates of surgery, escalated treatment, bowel damage progression, and disease relapse at 1 and 2 years. Regression analysis identified the 16-week EEN as the sole protective factor for early transmural healing and improved long-term outcomes. Combined treatment of biologics and 16-week EEN promotes early transmural healing, thereby enhancing long-term clinical outcomes in CD patients.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937075","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":"Cannabidiol Lacks Direct Effect on Cortical Excitability: A Randomized, Double Blind, Placebo Controlled, 3-Way Crossover Trial.","authors":"Andriy A Gorbenko, Catherine M K E de Cuba, Annika A de Goede, Titiaan E Post, Roman Bohoslavsky, Pamela K Strugala, Jules A A C Heuberger, Geert Jan Groeneveld","doi":"10.1002/cpt.70038","DOIUrl":"https://doi.org/10.1002/cpt.70038","url":null,"abstract":"<p><p>Cannabidiol (CBD) is approved as an adjunctive treatment of seizures associated with Dravet syndrome, Lennox-Gastaut Syndrome, and tuberous sclerosis. Its therapeutic and adverse effects are thought to arise, at least partly, from a pharmacokinetic interaction with clobazam, another anti-seizure medication (ASM). The goal of this study was to evaluate the intrinsic anti-epileptic and sedative properties of CBD. A randomized, double-blind, placebo-controlled, 3-way crossover trial was conducted in 25 healthy males. On each visit, single doses of 30 mg CBD, 700 mg CBD, or placebo were administered orally. The effects of CBD on cortical excitability were measured using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG). Sedative properties were assessed using a validated CNS test battery. Pharmacokinetic sampling was performed. Data were analyzed using a mixed-effects model. CBD did not have significant effects on single pulse and paired pulse TMS-EMG parameters, compared to placebo. Some significant clusters were seen on paired pulse TMS-EEG at 3 hours post-dose for 30 mg CBD, and at 3 and 5 hours post-dose for 700 mg CBD. CBD did not have significant effects on any tests assessing its sedative properties. These results suggest that CBD may lack intrinsic anti-epileptic and sedative properties and that its effects could be primarily a product of interactions with other drugs, notably clobazam.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936786","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":"Clinical Trials With Pragmatic Elements: A Review of Use Cases and Real-World Data Utilization.","authors":"Le Su, Lei Chen, Seema Betigeri, Nancy Dreyer, Helga Gardarsdottir, Rachele Hendricks-Sturrup, Mehmet Burcu","doi":"10.1002/cpt.70033","DOIUrl":"10.1002/cpt.70033","url":null,"abstract":"<p><p>Clinical trials with pragmatic elements can capture diverse patient populations, enable efficient follow-up, and reflect routine clinical practices; yet there is limited understanding of their design features, characteristics, and use of real-world data (RWD). Based on a targeted search of PubMed/EMBASE (Jan-2016 to Jul-2024), a review was conducted to characterize clinical trial use cases with pragmatic elements during the design and conduct of trials, as well as clinical trials that utilized RWD for long-term follow-up in the extension phase of the original (\"parent\") trial. A total of 27 use cases were characterized. There were 22 use cases with pragmatic elements, and nearly all employed randomization (n = 21, 95.5%), open-label design (n = 20, 90.9%), with usual/standard of care (n = 13, 59.1%) as comparators. Most generated evidence on both effectiveness and safety (n = 18, 81.8%), primarily in diabetes and cardiovascular disease areas (n = 14, 63.6%). The most common pragmatic elements were broad eligibility criteria, flexible treatment management, minimal or no follow-up, and streamlined endpoint collection. RWD (including electronic health records, claims, registries) was utilized in half of the use cases (n = 4 to enrich trial data with additional information abstracted from RWD; n = 7 to embed trials within routine healthcare databases/systems). In addition, 5 use cases were identified that utilized RWD in the extension phase of the original \"parent\" trials (4 utilizing RWD for long-term follow-up purposes, and one utilizing RWD to construct external controls for clinical trial infrastructure-based extension study). This review underscores the emerging role of pragmatic elements in enhancing trial efficiency, generalizability, and evidence generation on long-term outcomes.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870521","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":"FDA Adverse Event Reporting System Essentials: A Reflection on Study Conception","authors":"Emanuel Raschi,&nbsp;Paola Cutroneo,&nbsp;Francesco Salvo,&nbsp;Marco Tuccori,&nbsp;Charles Khouri","doi":"10.1002/cpt.70041","DOIUrl":"10.1002/cpt.70041","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881794","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":"Developing and Refining the Pregnancy Algorithm CErtaInty Tool (ACE-IT) for Validating Pregnancy Outcomes.","authors":"Sonal Singh, Hsiao-Ching Huang, Susan E Andrade, Lesley Butler, Sangmi Kim, Maryline Le Noan-Lainé, Simone Pinheiro, Laura Shaughnessy, Ollie Desrochers, Carla Rodriguez-Watson","doi":"10.1002/cpt.70036","DOIUrl":"https://doi.org/10.1002/cpt.70036","url":null,"abstract":"<p><p>Algorithm validation studies of health outcomes using real-world data are used to generate real-world evidence. We developed the Algorithm CErtaInty Tool (ACE-IT) to enable users to appraise whether a given real-world data-based algorithm is fit for purpose for a specific decision context, using the outcome of ischemic stroke as an exemplar. Our objective was to refine, develop, and tailor the ACE-IT to address whether validated algorithms for pregnancy and birth outcomes are fit for purpose for a specific decision context. We also tested the feasibility, acceptability, appropriateness, and content validity of the Pregnancy ACE-IT for the evaluation of an algorithm on pregnancy/birth outcomes. We engaged an expert panel of pharmacoepidemiologists and regulators to guide the development of the Pregnancy ACE-IT. The panel contributed to crafting a vignette on the selected pregnancy outcome of neural tube defects. Twenty-seven external raters used the Pregnancy ACE-IT to appraise whether a selected peer-reviewed algorithm to identify neural tube defects was fit for purpose and generalized as a target data source. Most raters found the Pregnancy ACE-IT acceptable and appropriate, although some did not find it easy to use. The Pregnancy ACE-IT represents a suitable, flexible, acceptable, and appropriate tool with relevant content for determining whether algorithms for pregnancy outcomes are fit for purpose for a specific decision context. Future studies to encourage broader acceptance and improve ease of use will require familiarizing users with the tool's operational characteristics and evaluating its suitability in the context of additional pregnancy/birth outcomes in different therapeutic areas.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870522","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":"Emulating Six Cardiovascular Outcome Trials of Antidiabetic Drugs in Individuals with Type 2 Diabetes: Analyses Based on Real-World Databases from Korea and Taiwan.","authors":"Hwa Yeon Ko, Philip C M Au, Michael Chun-Yuan Cheng, Ching-Lung Cheung, Ahhyung Choi, Miyuki Hsing-Chun Hsieh, Han Eol Jeong, Edward Chia-Cheng Lai, Brian Meng-Hsun Li, Kenneth K C Man, Jeremy A Rassen, Daniel Hsiang-Te Tsai, Shirley V Wang, Ian C K Wong, Ju-Young Shin, Sohee Park","doi":"10.1002/cpt.70027","DOIUrl":"https://doi.org/10.1002/cpt.70027","url":null,"abstract":"<p><p>With the increasing volume of clinical evidence derived from large-scale Asian real-world data (RWD) and the growing interest in its use in regulatory decision-making, it is important to conduct benchmarking exercises that evaluate whether studies using Asian RWD can generate similar conclusions as randomized controlled trials (RCTs). We aimed to assess whether observational studies based on Korea and Taiwan RWD can yield comparable results with trials by emulating six cardiovascular outcome trials (CVOTs) of antidiabetic drugs in individuals with type 2 diabetes (T2D). We emulated six CVOTs using nationwide claims of Korea and Taiwan. An active comparator, new-user design was applied, and observational analogues to the eligibility criteria and outcomes of the corresponding RCT were implemented. Propensity score matching was utilized to balance the treatment groups. Hazard ratios and 95% confidence intervals (CI) were estimated and compared with corresponding RCT estimates. We used three pre-specified binary agreement metrics that have been used in prior benchmarking studies to define concordance in results. Results from each of the six emulations were concordant with the corresponding CVOT on ≥ 1 binary agreement metric. Five out of six emulations indicated superiority when the corresponding CVOT only demonstrated non-inferiority. Results from emulations were more concordant with Asian-specific results from RCT, with four emulations meeting all agreement metrics. In this binational study using two Asian healthcare claims data, emulations yielded comparable clinical conclusions with the corresponding RCT, increasing the confidence in the validity of RWE studies in patients with T2D using these databases.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870523","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":"Re-Evaluation of Fixed Dosing Versus Body Size-Based Dosing Approaches for Large Molecule Therapeutics in Adults.","authors":"Andrew B SyBing, Huili Chen, Diane D Wang","doi":"10.1002/cpt.70015","DOIUrl":"https://doi.org/10.1002/cpt.70015","url":null,"abstract":"<p><p>Wang et al.¹ (2009) and Zhang et al.² (2011) recommended a fixed dosing approach for large molecule therapeutics for first-in-human (FIH) trials, based on the finding that the majority of α values (body size effect on clearance) were < 0.5 across 12 monoclonal antibodies (mAbs) and 18 therapeutic proteins (TPs) and peptides, and fixed dosing provides advantages such as convenience, reduced medical errors, and cost-effectiveness. They also recommended that the approved dosing approach should be determined by α and the therapeutic window. This review aims to re-evaluate these recommendations using a larger dataset (N = 143) of diverse molecules. Results showed 62% (78/126) of non-ADC drugs were approved with fixed dosing, and 58% (28/48) of non-ADC drugs approved with body size-based dosing had an α < 0.7 where fixed dosing would be appropriate. Therefore, only the remaining 16% (20/126) of non-ADC drugs required body size-based dosing. In addition, the FIH dosing approach had significant implications on the approved dosing approach with 68% (90/133) of drugs using the same dosing approach in FIH and approval. Lastly, of non-ADC drugs evaluated, 56% (71/126) demonstrated a relationship between α and the approved dosing approach. When α did not explain the approved dosing approach, lack of clinically meaningful differences in exposure (49%, 27/55) was the most common justification. These findings confirm Wang et al.'s and Zhang et al.'s previous conclusions, continuing to support their recommendations. Based on these insights, a decision tree is proposed for selecting the appropriate dosing approach at each stage of drug development.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858669","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":"Highlighted Articles","authors":"","doi":"10.1002/cpt.70009","DOIUrl":"10.1002/cpt.70009","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 3","pages":"535-536"},"PeriodicalIF":5.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843661","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":"Malthus-Informed Drug Development (MIDD)","authors":"Piet H. van der Graaf","doi":"10.1002/cpt.70019","DOIUrl":"10.1002/cpt.70019","url":null,"abstract":"&lt;p&gt;The 19th century scholar Thomas Robert Malthus is widely regarded as the founder of the discipline of population modeling, although 600 years before him, Leonardo of Pisa (more widely known as Fibonacci) presented a mathematical model to describe the growth of rabbits. In his &lt;i&gt;Essay on the Principle of Population&lt;/i&gt;, Malthus presented a simple model that describes how the human population grows exponentially, whereas food production can only increase linearly. The predictions of this model, which became known as “Malthusian catastrophes,” are grim: cycles of population growth inevitably followed by famine and collapse.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Malthus' original model has been the subject of intense debate, and its flaws are widely recognized. Despite its obvious shortcomings, the Malthus model has been the basis for foundational work in a variety of scientific areas such as economics, demographics, and climate change.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; However, the impact of Malthus' work in clinical pharmacology has not received much attention, although it can be argued that several fundamental pharmacokinetic–pharmacodynamic (PKPD) principles have, at least indirectly, their roots in it.&lt;/p&gt;&lt;p&gt;For example, after the publication of Malthus' original work, it was soon agreed that growth is typically not unbounded but capped by a maximum population size. This insight was the basis for Pierre François Verhulst to introduce the logistic growth model, which included a “carrying capacity”—the maximum population size that an environment can sustainably support. The logistic equation proposed by Verhulst is the basis for the most widely used model in pharmacology and PKPD, often referred to as the &lt;i&gt;E&lt;/i&gt;&lt;sub&gt;max&lt;/sub&gt; model or Hill equation, which is equivalent to equations proposed by, amongst others, Langmuir and Michaelis–Menten in the fields of chemistry and enzymology.&lt;span&gt;&lt;sup&gt;1, 3-5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Another main branch that developed from the Malthus model was the work from Lotka and Volterra, who independently derived what has become known as the “predator–prey” model, adding a second species to the Malthusian population mix.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; These models became the basis for studying and predicting drug effects in infectious diseases caused by, for example, human immunodeficiency virus (HIV), hepatitis B (HBV) and C virus (HCV), and coronaviruses (&lt;b&gt;Figure&lt;/b&gt; 1).&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; For example, in their seminal paper, Neumann and co-workers proposed a basic model of viral infection based on Malthusian principles to unravel the dynamics of HCV and the mechanism of action of interferon.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; This work became the foundation for model-informed drug development (MIDD) in HCV and has been widely used to optimize clinical trial design and individualized dosing (&lt;b&gt;Figure&lt;/b&gt; 2).&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In the current issue of &lt;i&gt;Clinical Pharmacology &amp; Therapeutics&lt;/i&gt; (&lt;i&gt;CPT&lt;/i&gt;), Cortés-Rio &lt;i&gt;e","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 3","pages":"531-534"},"PeriodicalIF":5.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843660","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}