Clinical Pharmacology & Therapeutics最新文献

{"title":"Clinical Pharmacogenetics Implementation Consortium Guideline for NAT2 Genotype and Hydralazine Therapy.","authors":"Michael T Eadon, David W Hein, Michael A Andersen, Arlene B Chapman, Rhonda M Cooper-DeHoff, Zeruesenay Desta, Julio D Duarte, Amanda L Elchynski, Andrea Gaedigk, Seth E Karol, Nita A Limdi, Christelle Lteif, Laura Sosinski, Pablo Zubiaur, Michelle Whirl-Carrillo, Teri E Klein, Kelly E Caudle, Roseann S Donnelly, José A G Agúndez","doi":"10.1002/cpt.70071","DOIUrl":"https://doi.org/10.1002/cpt.70071","url":null,"abstract":"<p><p>Hydralazine is a vasodilator typically used in the treatment of resistant hypertension and heart failure. N-acetyltransferase 2 (NAT2) catalyzes the metabolism of hydralazine into inactive metabolites. NAT2 poor metabolizers (historically referred to as \"slow acetylators\") are predicted to have increased plasma hydralazine concentrations compared with NAT2 rapid and intermediate metabolizers (historically referred to as \"rapid acetylators\" and \"intermediate acetylators,\" respectively), which may lead to both increased clinical efficacy and adverse effects, including drug-induced systemic lupus erythematosus. This guideline summarizes the evidence from the literature relevant to NAT2/hydralazine and provides recommendations for hydralazine prescribing based on NAT2 genotype-predicted acetylator phenotype (updates at www.cpicpgx.org).</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090737","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.70051","DOIUrl":"10.1002/cpt.70051","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"759-760"},"PeriodicalIF":5.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101174","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":"Reply to \"High Pharmacokinetic Variability and Unrecognized Limitations in First-Line Osimertinib Plus Chemotherapy for EGFR-Mutated NSCLC\".","authors":"Azar Shahraz, Jincheng Yang, Diansong Zhou, Karthick Vishwanathan, Dana Ghiorghiu, Yuri Rukazenkov, Aarti Sawant-Basak","doi":"10.1002/cpt.70068","DOIUrl":"https://doi.org/10.1002/cpt.70068","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068754","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":"Interchanging Biosimilars Using Proteomics","authors":"Piet H. van der Graaf,&nbsp;Ingolf Cascorbi","doi":"10.1002/cpt.70032","DOIUrl":"10.1002/cpt.70032","url":null,"abstract":"&lt;p&gt;The development and implementation of bioequivalence (BE) approaches can be considered one of the major innovations in clinical pharmacology.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Before the 1984 Waxman-Hatch Act (Drug Price Competition and Patent Term Restoration Act) created the Abbreviated New Drug Application as a regulatory approval path using BE, only 19% of drugs prescribed in the United States (US) were generic. This number has now increased to ~90%, saving society and the healthcare system trillions of dollars and making treatments available to patients across the world who could previously not afford them.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Because exact molecular copies cannot be made of a biological therapeutic, there is no such thing as a “generic biological.” Even if the amino acid sequence of a therapeutic protein is completely identical, there may be changes in the glycosylation pattern, differences in protein folding or oxidation or deamination, changes at the start or end of the protein (e.g., loss of terminal amino acids through enzymatic processes) or changes in the grade of aggregation. Therefore, demonstrating BE alone is not sufficient to claim biosimilarity. As a result, randomized, controlled non-inferiority or equivalence studies must generally be conducted to demonstrate the efficacy and safety of the biosimilar compared to the original, making the path to approval complex and costly.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The best we can aim to achieve is a “biosimilar”: a biological product that is highly similar to and has no clinically meaningful differences from an approved reference product.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;As a result, despite the significant shift in recent decades from small molecules drugs to biotherapeutics in drug development and clinical practice, most biologicals do not have an approved biosimilar. There is therefore a huge need to make biosimilar development and approval more efficient, streamlined, and cheaper. Achieving this through clinical pharmacology innovations will be a future milestone of major impacts of our discipline and elevate pharmaco-equity in global healthcare.&lt;/p&gt;&lt;p&gt;The importance of this topic was illustrated by the January 2023 issue of &lt;i&gt;Clinical Pharmacology &amp; Therapeutics&lt;/i&gt; (&lt;i&gt;CPT&lt;/i&gt;), which was entirely dedicated to the theme of “Advancing Innovations in Biosimilars.”&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The paper by Chekka and colleagues from the US Food and Drug Administration (FDA) in the current issue (&lt;b&gt;Figure&lt;/b&gt; 1) reports the latest innovation in regulatory science and how proteomic pharmacodynamic (PD) biomarkers can be used in biosimilarity assessment to reduce the need for comparative clinical efficacy studies.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; The authors analyzed candidate proteins from longitudinal plasma samples from healthy subjects who received interferon (IFN)β-1a or pegylated (peg)IFNβ-1a. Several hundred candidates were differentially expressed compared to the placebo and nine were pri","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"757-758"},"PeriodicalIF":5.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068735","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":"The Feasibility and Quality of the European Prescribing Exam: An International Multicenter Pilot Study Among 3109 Medical Students From 16 Medical Schools.","authors":"Erik M Donker, Joost D Piët, David J Brinkman, Milan C Richir, Paraskevi Papaioannidou, Robert Likic, Emilio J Sanz, Thierry Christiaens, João N Costa, Fabrizio De Ponti, Ylva Böttiger, Cornelis Kramers, Michiel A van Agtmael, Jelle Tichelaar","doi":"10.1002/cpt.70063","DOIUrl":"https://doi.org/10.1002/cpt.70063","url":null,"abstract":"<p><p>The WHO Global Patient Safety Challenge \"Medication Without Harm\" emphasizes the need to improve doctors' prescribing competence. Junior doctors are particularly at risk of prescribing errors due to inadequate training. To address this, the European Prescribing Exam was developed to standardize and improve clinical pharmacology and therapeutics (CPT) education across Europe. This study describes the development and quality analysis of the first two pilot examinations. Based on European consensus studies and the Dutch National Pharmacotherapy Assessment, an assessment blueprint was developed. Two pilot examinations, each with 36 knowledge-based and 11 skills-based questions, were administered between 2020 and 2023 at 16 medical schools in 11 countries. We assessed exam quality through reliability (standard error of measurement, Cronbach's alpha, item-rest correlations (R_ir-value), difficulty index (DI)), and content validity (content validity ratio's (CVR)). Questions with a negative R_ir or CVR, or DI < 0.44 were flagged as potential lower quality. In addition, students' scores (% of maximum) and differences between schools and curricula were evaluated. A total of 3109 students participated (Examination 1: 1371; Examination 2: 1745). Most questions were of high quality; 20/94 (21.3%) were flagged. Median scores on the examinations were 66.2% (IQR 55.4-74.3) and 58.9% (IQR 52.1-65.8) for pilot 1 and 2, respectively. Students from schools with problem-based learning or a national prescribing examination scored significantly higher (P < 0.001). In conclusion, this study demonstrates the feasibility of a standardized European Prescribing Exam. However, the wide variation and generally low median scores highlight the need to improve and harmonize CPT education across Europe.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068729","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":"High Pharmacokinetic Variability and Unrecognized Limitations in First-Line Osimertinib Plus Chemotherapy for EGFR-Mutated NSCLC.","authors":"Shiuan-Chih Chen, Ming-Cheng Lin","doi":"10.1002/cpt.70069","DOIUrl":"https://doi.org/10.1002/cpt.70069","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051482","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":"UGT1A1 and Sacituzumab Govitecan Toxicity: A Systematic Review and Meta-Analysis.","authors":"Cinzia Dello Russo, Innocent Gerald Asiimwe, Sudeep Pushpakom, Carlo Palmieri, Munir Pirmohamed","doi":"10.1002/cpt.70060","DOIUrl":"https://doi.org/10.1002/cpt.70060","url":null,"abstract":"<p><p>Sacituzumab govitecan (SG), a humanized antibody-drug conjugate, enables intra-tumor delivery of SN-38, the active metabolite of irinotecan, with the aim of increasing efficacy. SN-38 is predominantly inactivated by the polymorphically expressed uridine diphosphate glucuronosyltransferase 1A1 (UGT1AA) where reduced activity can lead to toxicity. SG toxicity closely resembles that of irinotecan. We conducted a systematic review and meta-analysis (PROSPERO ID: CRD42024598820) to assess UGT1A1 genotype as a determinant of SG toxicity. Studies published up to September 29, 2024, on UGT1A1 genotype and SG toxicity were eligible. Risk of bias was assessed using the STROPS guideline. Effect estimates for each genotype, comparing heterozygotes and homozygotes to wild-type, were analyzed. Odds ratios (ORs) with 95% Confidence Intervals (CIs) and forest plots were generated for each exposure-outcome combination. Four clinical trials including 999 UGT1A1 genotyped subjects were selected for the meta-analysis. SG treatment in UGT1A1*28 homozygous subjects increased the risk of toxicity. The OR (95% CI) was 1.80 (1.03-3.14) for neutropenia, 1.38 (0.90-2.10) for diarrhea, and 1.62 (1.07-2.45) for anemia of any grade, with low heterogeneity (I² ≤ 28%). The OR for all severe (grade ≥ 3) toxicities combined was 7.03 (95% CI: 3.41-14.50, I² = 18%). UGT1A*28 homozygous subjects were more likely to have dose reductions and treatment interruptions compared to wild-type individuals. In conclusion, individuals with UGT1A*28/*28 genotype are at an increased risk of severe SG-related toxicity. Pre-treatment genotyping should be used to identify individuals that may benefit from personalized dosing, closer monitoring or alternative therapies.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038660","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":"Off-the-Shelf Large Language Models for Guiding Pharmacoepidemiological Study Design.","authors":"Gerard Ompad, Keele Wurst, Darmendra Ramcharran, Anders Hviid, Andrew Bate, Maurizio Sessa","doi":"10.1002/cpt.70039","DOIUrl":"https://doi.org/10.1002/cpt.70039","url":null,"abstract":"<p><p>This study aimed to assess the ability of two off-the-shelf large language models, ChatGPT and Gemini, to support the design of pharmacoepidemiological studies. We assessed 48 study protocols of pharmacoepidemiological studies published between 2018 and 2024, covering various study types, including disease epidemiology, drug utilization, safety, and effectiveness. The coherence (i.e., \"Is the response coherent and well-formed, or is it difficult to understand?\") and relevance (i.e., \"Is the response relevant and informative, or is it lacking in substance?\") of the large language models' responses were evaluated by human experts across seven key study design components. Coding accuracy was assessed. Both large language models demonstrated high coherence, with over 90% of study components rated as \"Strongly agree\" by experts for most categories. ChatGPT achieved the highest coherence for \"Index date\" (97.9%) and \"Study design\" (95.8%). Gemini excelled in \"Study outcome\" (93.9%) and \"Study exposure\" (95.9%). Relevance, however, was more variable, with ChatGPT aligning with expert recommendations in over 90% of cases for \"Index date\" and \"Study design\" but showing lower agreement for covariates (65%) and follow-up (70%). Coding agreement percentages reveal varying levels of concordance, with the Anatomical Therapeutic Chemical classification system coding system demonstrating the highest agreement at 50% with experts. In contrast, the Current Procedural Terminology and International Classification of Diseases systems showed agreements of 22.2% and 20%, respectively. While ChatGPT and Gemini show promise in certain tasks supporting pharmacoepidemiological study design, their limitations in relevance and coding accuracy highlight the need for critical oversight by domain experts.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032541","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":"Nonsteroidal Anti-Inflammatory Drugs and Risk of Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.","authors":"Abdelrahman G Tawfik, Ainhoa Gomez-Lumbreras, Guilherme Del Fiol, Kensaku Kawamoto, Katy E Trinkley, Thomas Reese, Aubrey Jones, Daniel C Malone","doi":"10.1002/cpt.70054","DOIUrl":"https://doi.org/10.1002/cpt.70054","url":null,"abstract":"<p><p>Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain and inflammation but are associated with gastrointestinal (GI) bleeding. While this risk is well established, most studies evaluate NSAIDs as a homogenous class, limiting clinical decision-making based on individual agent safety. This systematic review and meta-analysis aimed to quantify the risk of GI bleeding associated with individual NSAIDs. We searched PubMed from inception through January 2025 using MeSH and free-text terms for \"gastrointestinal bleeding\" and nine commonly used NSAIDs. A random effects meta-analysis was conducted to estimate the pooled odds ratios (ORs) for GI bleeding, with hazard ratios (HRs) and relative risks (RRs) treated as approximations of ORs due to the rare event nature of GI bleeding. Of 6,711 records screened, 25 studies met the inclusion criteria. Substantial heterogeneity in study design, populations, and outcome ascertainment was observed. Celecoxib was associated with the lowest risk of GI bleeding (OR 1.16, 95% CI: 0.84-1.61). Among non-selective NSAIDs, ibuprofen had the lowest significant risk (OR 2.28, 95% CI: 1.71-3.03), while ketorolac showed the highest risk (OR 20.67, 95% CI: 14.56-29.34). Other agents, such as piroxicam and meloxicam, also demonstrated significantly elevated risks. The risk of GI bleeding varies widely among individual NSAIDs. Celecoxib appears to have the lowest GI risk, though cardiovascular safety must also be considered. These findings highlight the need for personalized NSAID selection and suggest that NSAIDs should not be treated as a uniform class when assessing bleeding risk.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013537","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":"The Silver Tsunami Prescription: A Comprehensive Analysis of Approval Delays and Innovation Assessment in China's Novel Geriatric Drugs (2005-2024).","authors":"Yang Xu, Haibo Wei, Qixiang Guo, Jing Ding, Yue Yang","doi":"10.1002/cpt.70047","DOIUrl":"https://doi.org/10.1002/cpt.70047","url":null,"abstract":"<p><p>This cross-sectional study aims to demonstrate the impact of China's 2015 review and approval reform on the delays in market entry for novel geriatric drugs, as well as the capability of domestic innovation in developing geriatric drugs. We analyzed the novel geriatric drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2024 to assess the drug lags in China by using the EU and Japan as comparators. During this period, the FDA approved a total of 183 novel drugs targeting geriatric diseases, of which 109 were also approved by the NMPA. Post-reform, China's absolute approval lag decreased significantly, with median relative lag narrowing from 53.9 to 29.9 months. However, China's lag remained longer than the EU and Japan, driven by submission delays. Domestic innovative drug approvals surged post-reform, yet oncology dominated, overshadowing high-burden conditions like neurological disorders, cardiovascular disease, and respiratory diseases. Expedited programs reduced development duration (conditional approval: 49.4 vs. regular 70.9 months), but review times lagged behind the FDA (16.1 vs. 11.1 months). This study also discusses the considerations of China's regulatory agency regarding current issues in geriatric drug development and future regulatory plans. Future regulatory efforts in China should focus on promoting patient-centric approaches, optimizing trial designs (including clinical pharmacology modeling and artificial intelligence), and incorporating real-world evidence to address the unique needs of older adults. These measures will be crucial in ensuring equitable access to innovative therapies and mitigating the impact of the \"silver tsunami\" on health outcomes for China's rapidly aging population.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013534","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}