Clinical Pharmacology & Therapeutics最新文献

{"title":"Microbiome-Informed Dosing: Exploring Gut Microbial Communities Impact on Mycophenolate Enterohepatic Circulation and Therapeutic Target Achievement.","authors":"Abdelrahman Saqr, Shen Cheng, Mahmoud Al-Kofahi, Christopher Staley, Pamala A Jacobson","doi":"10.1002/cpt.3740","DOIUrl":"https://doi.org/10.1002/cpt.3740","url":null,"abstract":"<p><p>Pharmacomicrobiomics is an emerging field due to important microbiome effects on pharmacokinetics and clinical outcomes. However, the application of this knowledge remains limited. Mycophenolic acid (MPA) is the primary active metabolite of the immunosuppressant, mycophenolate mofetil (MMF). MPA undergoes glucuronidation to form MPA glucuronide (MPAG) which is deglucuronidated by bacterial β-glucuronidases and reformed as MPA through enterohepatic circulation (EHC). We studied the stool microbiome effect on the pharmacokinetics of MPA, its metabolites, and EHC in hematopoietic cell transplant (HCT) recipients using a semi-mechanistic population pharmacokinetic model. Microbiome communities were identified using correlation network analysis, and their impact on pharmacokinetics was assessed using full fixed-effects modeling. Simulations were then conducted to evaluate MMF dosing regimens and to assess the impact of community abundance on EHC and MPA therapeutic target achievement. High abundance of Bacteroides uniformis-dominant and Bacteroides vulgatus-dominant communities was associated with higher EHC and an increase in MPA exposure. Low abundance of these communities was associated with a 52-80% and 4-83% lower EHC and MPA exposure, respectively. Simulations showed 70% of individuals with low abundance of these communities achieved the therapeutic target at the typical HCT MMF dose of 1,000 mg Q8 hours IV; however, ≥ 95% were within the therapeutic target at 1,250 mg Q8 hours or 1,750 mg Q12 hours. EHC accounted for 34% of the MPA area under the curve. Elimination of EHC reduced troughs by 100%. This work quantifies the microbiome's effect on pharmacokinetics, paving the way for future microbiome-informed dosing to optimize therapeutic target attainment.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293005","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":"FRAME: Framework for Real-World Evidence Assessment to Mitigate Evidence Uncertainties for Efficacy/Effectiveness – An Evaluation of Regulatory and Health Technology Assessment Decision Making","authors":"Gianmario Candore,&nbsp;Claire Martin,&nbsp;Mack J. Mills,&nbsp;Annabel Suter,&nbsp;Anna Lloyd,&nbsp;Danitza Chavez-Montoya,&nbsp;Diego Civitelli,&nbsp;Birgit Wolf,&nbsp;Paul Bolot,&nbsp;Juergen Wasem,&nbsp;Montse Soriano Gabarró,&nbsp;Panos G. Kanavos,&nbsp;Mark Sculpher","doi":"10.1002/cpt.3713","DOIUrl":"10.1002/cpt.3713","url":null,"abstract":"<p>Real-World Evidence (RWE) is increasingly used in submissions to regulatory agencies and health technology assessment bodies (HTAbs) to support the efficacy and effectiveness of new medicines and indications. However, there is limited information on the RWE characteristics that impact its role in approval and reimbursement decisions. To investigate these characteristics, we developed FRAME: a Framework for Real-world evidence Assessment to Mitigate Evidence uncertainties for efficacy/effectiveness. We compiled a list of medicinal product indications where RWE supported the efficacy of interventional trials or assessed effectiveness in observational settings. FRAME was applied to a prioritized subset of these submissions to authorities from North America, Europe, and Australia. For each product indication, we extracted information on characteristics describing the submission, clinical context, strength of evidence, and process factors from publicly available assessment reports. Of the 87 identified medicinal product indications, 15 were prioritized, covering 68 submissions and 76 RWE studies across 11 authorities in scope. Four main results emerged: (i) low granularity within assessment reports on the analyzed variables, limiting the learnings from analyzing them; (ii) variability in how RWE was assessed within and across regulatory agencies and HTAbs; (iii) a positive association between the proportion of positive comments from authorities on RWE studies and their impact on decision making. Particularly, a large effect size was consistently noted when RWE was considered primary evidence; and (iv) limited use of advanced RWE study designs. These findings support five recommendations to enhance shared learning on RWE, clarify its evidentiary value, and generate evidence to better support authorities' decision making.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 3","pages":"649-661"},"PeriodicalIF":5.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3713","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256969","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":"Repurposing Acebutolol for Osteoporosis Treatment: Insights From Multi-Omics and Multi-Modal Data Analysis.","authors":"Dan-Yang Liu, Hui Shen, Jonathan Greenbaum, Qiao-Rong Yi, Shuang Liang, Yue Zhang, Jia-Chen Liu, Chuan Qiu, Lan-Juan Zhao, Qing Tian, Kuan-Jui Su, Zhe Luo, Li Wu, Xiang-He Meng, Hong-Mei Xiao, Yun Deng, Yang Li, Dragana Lovre, Vivian Fonseca, Fernando L Sanchez, Li-Jun Tan, Hong-Wen Deng","doi":"10.1002/cpt.3738","DOIUrl":"10.1002/cpt.3738","url":null,"abstract":"<p><p>Osteoporosis is a common metabolic bone disease with aging, characterized by low bone mineral density (BMD) and higher fragility fracture risk. Although current pharmacological interventions provide therapeutic benefits, long-term use is limited by side effects and comorbidities. In this study, we employed driver signaling network identification (DSNI) and drug functional networks (DFN) to identify repurposable drugs from the Library of Integrated Network-Based Cellular Signatures. We constructed osteoporosis driver signaling networks (ODSN) using multi-omics data and developed DFN based on drug similarity. By integrating ODSN and DFN with drug-induced transcriptional responses, we screened 10,158 compounds and identified several drugs with strong targeting effects on ODSN. Mendelian randomization assessed potential causal links between cis-eQTLs of drug targets and BMD using genome-wide association study data. Our findings indicate four drugs, including Ruxolitinib, Alfacalcidol, and Doxercalciferol, may exert anti-osteoporosis effects. Notably, Acebutolol, a β-blocker for hypertension, has not previously been implicated in osteoporosis therapy. For validation, zebrafish osteoporosis models were established using Dexamethasone-induced bone loss, followed by treatment with Acebutolol hydrochloride and Alfacalcidol. Both compounds demonstrated significant protective effects against osteoporosis-related bone deterioration. Furthermore, a population-based data set, utilizing propensity score matching and analyzed via a generalized linear model, revealed that individuals taking β-blocker drugs exhibited significantly higher BMD than users of other cardiovascular medications. In summary, this study integrates multi-omics approaches, experimental validation, and real-world population data to propose acebutolol as a novel candidate for osteoporosis treatment. These findings warrant further mechanistic studies and clinical trials to evaluate its efficacy in osteoporosis management.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232781","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":"Use of PopPK and E-R Analyses toward Explaining Causal Link Between ADAMTS13 in Recombinant vs. Plasma-Based Therapies and Clinical Effects in cTTP","authors":"Munjal Patel,&nbsp;Huijuan Xu,&nbsp;Olivier Barriere,&nbsp;Paul Diderichsen,&nbsp;Parth Patwari,&nbsp;Andy Z. X. Zhu,&nbsp;Jean François Marier,&nbsp;Thomas Peyret,&nbsp;Linda T. Wang,&nbsp;Björn Mellgård,&nbsp;Wenping Wang,&nbsp;Indranil Bhattacharya","doi":"10.1002/cpt.3720","DOIUrl":"10.1002/cpt.3720","url":null,"abstract":"<p>Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, potentially life-threatening condition caused by a deficiency of the blood enzyme ADAMTS13. Until now, ADAMTS13 replacement has been achieved with infusions of plasma or plasma-based therapies (PBT). However, the quantitative relationship between ADAMTS13 plasma activity and clinical manifestations is poorly understood. We therefore conducted integrated population pharmacokinetics (PopPK) analysis and exposure–response modeling based on three clinical trials of recombinant ADAMTS13 (rADAMTS13, Takeda Pharmaceuticals U.S.A., Inc.) in patients with cTTP. These aim to assess the clinical benefit of rADAMTS13, which at the proposed dose of 40 IU/kg provides ADAMTS13 peak levels of approximately 100% of normal levels. The PK model indicated that, besides body weight–based dosing, no further dose adjustment was required based on age or race. The only extrinsic covariates with a significant impact on ADAMTS13 plasma activity levels were dosing interval and treatment type (rADAMTS13 vs. PBT). The correlation between ADAMTS13 plasma activity levels and cTTP manifestations was investigated with three different exposure<b>–</b>response models. Increasing exposure to ADAMTS13, as measured by average activity over a one-to-two-week period, predicted the probability of disease manifestations, primarily assessed as thrombocytopenia. Model simulations predicted that &gt;90% of patients treated with 40 IU/kg rADAMTS13 achieve an average ADAMTS13 plasma activity &gt;13% of normal, which was shown to be highly protective against thrombocytopenia (&gt;70% lower hazard). Similar results were observed for protection against elevation of lactate dehydrogenase, a marker of microangiopathic hemolytic anemia. Overall, these results support the use of rADAMTS13 treatment for patients with cTTP.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"813-822"},"PeriodicalIF":5.5,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223850","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":"Using Quantitative Approaches to Optimize Dosages for New Combinations and Subsequent Indications for Oncology Drugs","authors":"Wei Gao,&nbsp;Jiang Liu,&nbsp;Cynthia J. Musante,&nbsp;Hao Zhu,&nbsp;Matthew Thompson,&nbsp;Mirat Shah,&nbsp;Yanguang Cao,&nbsp;Vijay Ivaturi,&nbsp;Mark R. Conaway,&nbsp;Dean Bottino,&nbsp;Donghua Yin,&nbsp;Dorothee Semiond,&nbsp;Aram Oganesian,&nbsp;Mark J. Ratain,&nbsp;Chunze Li,&nbsp;Li Zhu,&nbsp;Ying C. Ou,&nbsp;Xiling Jiang,&nbsp;Jonathan Vallejo,&nbsp;Rajanikanth Madabushi,&nbsp;Qi Liu,&nbsp;Marc Theoret,&nbsp;Atiqur Rahman,&nbsp;Brian Booth,&nbsp;Olanrewaju Okusanya,&nbsp;Bernadette E. Johnson-Williams,&nbsp;Stacy S. Shord","doi":"10.1002/cpt.3725","DOIUrl":"10.1002/cpt.3725","url":null,"abstract":"<p>Ongoing efforts to optimize the dosages of oncology drugs have largely focused on the initial indication, with emphasis placed on maximizing the utility of all available evidence to improve dose finding, dose selection, and trial design; however, optimizing dosages for new combinations or subsequent indications is more complex and warrants further discussion. For example, the dose–response (DR) or exposure–response (ER) relationships can change when multiple drugs are used (combination therapies) and can differ between tumor types, patient populations, and treatment settings (subsequent indications). Quantitative approaches can help address the challenges of optimizing dosages for new combinations or subsequent indications. To further this dialogue, the US Food and Drug Administration's Office of Clinical Pharmacology and the International Society of Pharmacometrics co-sponsored a workshop to discuss the development of investigational and approved drugs in new combinations or for subsequent indications using model-informed approaches to investigate, support, and select optimized dosages for oncology drugs.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"772-777"},"PeriodicalIF":5.5,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223851","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":"Progress in Pharmacogenomics Implementation in the United States: Barrier Erosion and Remaining Challenges","authors":"D. Max Smith,&nbsp;Michael P. Douglas,&nbsp;Christina L. Aquilante,&nbsp;Patricia A. Deverka,&nbsp;Beth Devine,&nbsp;Henry M. Dunnenberger,&nbsp;Philip E. Empey,&nbsp;Daniel L. Hertz,&nbsp;Andrew A. Monte,&nbsp;Ann M. Moyer,&nbsp;Jai N. Patel,&nbsp;Victoria M. Pratt,&nbsp;Loren Saulsberry,&nbsp;Stuart A. Scott,&nbsp;Deepak Voora,&nbsp;Erica L. Woodahl,&nbsp;Michelle Whirl-Carrillo,&nbsp;Akinyemi Oni-Orisan,&nbsp;the Pharmacogenomics Global Research Network (PGRN) Publications Committee","doi":"10.1002/cpt.3736","DOIUrl":"10.1002/cpt.3736","url":null,"abstract":"<p>Barriers to incorporating pharmacogenetics into routine clinical practice in the United States are well documented. Initial surveys by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2009 and 2010 identified barriers across four key domains that have hindered the widespread adoption of clinical pharmacogenetic testing. These are presented verbatim as: (i) absence of a definition of the processes required to interpret genotype information and to translate genetic information into clinical actions; (ii) need for recommended drug/gene pairs to implement clinically now; (iii) clinician resistance to consider pharmacogenetic information at the bedside; and (iv) concerns about test costs and reimbursement. Over time, many of these challenges have been overcome, and clinical pharmacogenetic testing has subsequently reached broader implementation. Despite this progress, several barriers remain that block further adoption. This narrative review used authors' expertise and experience to identify and describe current barriers to pharmacogenetic implementation across seven domains in the United States: equity and inclusion; guidelines and supporting evidence; regulatory agency oversight; payer coverage and insurance; availability of quality pharmacogenetic tests; electronic health records; and provider and patient education. Within each domain, it revisits past successes and challenges and explores remaining barriers. We also propose solutions to address ongoing challenges across these domains, including further expansion of recommendations beyond pharmacogenetic-specific guidelines, standards for designing clinical decision support tools, and broader pharmacogenetics education. Addressing these remaining obstacles directs work to enable broader adoption of clinical pharmacogenetic implementation to ultimately improve patient outcomes.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"778-789"},"PeriodicalIF":5.5,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223849","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":"CYP2C19 Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention in the Million Veteran Program","authors":"Catherine Chanfreau-Coffinier,&nbsp;Kevin A. Friede,&nbsp;Mary E. Plomondon,&nbsp;Kyung Min Lee,&nbsp;Zhenyu Lu,&nbsp;Tia Dinatale,&nbsp;Scott L. DuVall,&nbsp;Jason L. Vassy,&nbsp;Stephen W. Waldo,&nbsp;John H. Cleator,&nbsp;Thomas M. Maddox,&nbsp;Daniel J. Rader,&nbsp;Themistocles L. Assimes,&nbsp;Scott M. Damrauer,&nbsp;Philip S. Tsao,&nbsp;Kyong-Mi Chang,&nbsp;Deepak Voora,&nbsp;Julie A. Lynch,&nbsp;Jay Giri,&nbsp;VA Million Veteran Program,&nbsp;Sony Tuteja","doi":"10.1002/cpt.3741","DOIUrl":"10.1002/cpt.3741","url":null,"abstract":"<p><i>CYP2C19</i> loss-of-function (LOF) alleles decrease the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). The impact of genotype in patients undergoing PCI for stable ischemic heart disease (SIHD) in real-world populations is less clear. We determined time to major adverse cardiac event (MACE), defined as the composite of cardiovascular death, stroke, or myocardial infarction, within 12 months following PCI in the VA Million Veteran Program (MVP) participants treated with clopidogrel from 1/1/2009 to 9/30/2017. Among 9061 Veterans (mean age 66.4 ± 8.7 years, 98% male, 13% Black); 43% had ACS, 57% had SIHD, and 28% carried a <i>CYP2C19</i> LOF allele. In total, 619 patients (6.8%) experienced MACE, 317 (8.2%) in the ACS group and 302 (5.8%) in the SIHD group. Overall, a trend toward increased MACE risk was seen in the LOF carriers vs. non-carriers (adjusted hazard ratio [aHR] 1.13, confidence interval [95% CI] 0.98–1.31, <i>P</i> = 0.097), with a stronger risk among those presenting with ACS (aHR 1.20, 95% CI 0.98–1.47; <i>P</i> = 0.083). In post hoc analyses, LOF was associated with a significantly increased risk of MACE among younger (&lt; 66 years) patients with ACS (aHR 1.41 [1.04–1.91], <i>P</i> = 0.028); however, no difference in risk was observed among older patients (aHR 1.07, 95% CI 0.80–1.40, <i>P</i> = 0.676). There was no impact of genotype in patients with SIHD (aHR 1.09, 95% CI 0.82–1.44, <i>P</i> = 0.565). Clinical factors may be more important than <i>CYP2C19</i> genotype in determining the risk of MACE in older Veterans treated with clopidogrel undergoing PCI for ACS.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 4","pages":"876-884"},"PeriodicalIF":5.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207266","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":"Reply to: “Current Use of PBPK Modeling in New Medicinal Product Approvals at EMA: A Clinical Appraisal of Voclosporin in Lupus Nephritis”","authors":"Polly Paul,&nbsp;Pieter J. Colin,&nbsp;Flora Musuamba Tshinanu,&nbsp;Carolien Versantvoort,&nbsp;Efthymios Manolis,&nbsp;Kevin Blake","doi":"10.1002/cpt.3739","DOIUrl":"10.1002/cpt.3739","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 3","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214489","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":"Optimizing Patient Registries for Regulatory Decision Making - Key Learnings From an HMA/EMA Multistakeholder Workshop","authors":"Kelly Plueschke,&nbsp;Carla Jonker,&nbsp;Hanna Kankanen,&nbsp;Thorsten Vetter,&nbsp;Bruno Sepodes,&nbsp;Lutz Naehrlich,&nbsp;Jan Hillert,&nbsp;Gracy Crane,&nbsp;Sabine Straus,&nbsp;Paolo Foggi,&nbsp;Simona Martin,&nbsp;Christina Kyriakopoulou,&nbsp;Peter Mol,&nbsp;Francesca Day,&nbsp;Kieran Breen,&nbsp;Neil Bennett,&nbsp;Mencia de Lemus Belmonte,&nbsp;Simon Bennett,&nbsp;Patrice Verpillat,&nbsp;Kit C. B. Roes,&nbsp;Ana Cochino,&nbsp;Franz Schaefer,&nbsp;Jesús María Hernández-Rivas,&nbsp;Patricia McGettigan,&nbsp;Peter Arlett","doi":"10.1002/cpt.3733","DOIUrl":"10.1002/cpt.3733","url":null,"abstract":"<p>The Joint Heads of Medicines Agencies and European Medicines Agency's (HMA/EMA) big data initiative paves the way for better integration of real-world data, including data from patient registries, into regulatory decisions on medicines. This article focuses on the outcome of a two-day multistakeholder workshop organized by EMA in 2024, which explored ways to optimize the EMA qualification procedure for patient registries, and to establish the value and enable the use of these data across the full spectrum of research questions. Key recommendations include the need to clarify the aim, scope, and added value of the qualification of registries, coupled with a review of the procedural steps to ensure the process is fit-for-purpose to evaluate the use of registries in specific regulatory contexts. Further recommendations focused on strengthening interactions between stakeholders, as well as providing them with enhanced support by increasing awareness of publicly available tools that could leverage the potential of registry data, together with existing guidance. The European Medicines Regulatory Network is now working together with all relevant stakeholders, including the EMA scientific committees and working parties, the Joint HMA/EMA Network Data Steering Group and existing focus groups with external partners, to implement concrete actions that will address these recommendations. Among others, the update of existing guidance, the development of templates and Questions &amp; Answers documents, and the design of appropriate communication and stakeholder engagement plans will aid in achieving the common goal of making optimal use of patient registry data to support public health in the European Union.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 3","pages":"551-560"},"PeriodicalIF":5.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3733","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207267","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":"Model-Informed Drug Development-Based Bridging from Subcutaneous to Intravenous Secukinumab Dosing: Approval in Psoriatic Arthritis and Axial Spondyloarthritis","authors":"Thomas Dumortier,&nbsp;Guillermo Valenzuela,&nbsp;Melvin Churchill,&nbsp;Jelena Mijatovic,&nbsp;Gerard Bruin,&nbsp;Luminita Pricop,&nbsp;Hanno Richards,&nbsp;Didier Renard,&nbsp;Atul Singhal,&nbsp;Anshu Marathe","doi":"10.1002/cpt.3716","DOIUrl":"10.1002/cpt.3716","url":null,"abstract":"<p>The objective of this modeling and simulation analysis was to determine an intravenous (IV) secukinumab dosing regimen with steady-state exposure within the ranges of the approved subcutaneous (SC) regimens (300 and 150 mg every 4 weeks [q4w]) and to predict the efficacy and safety of this IV regimen for patients with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA). This approach was suggested by the US Food and Drug Administration (FDA) following review of the primary endpoint analysis results of secukinumab 3 mg/kg q4w IV in patients with PsA (INVIGORATE-2 study). Noting the higher exposure of the investigated IV regimen compared to the approved SC regimens, the FDA considered that the INVIGORATE-2 data available through Week 16 only may not convey sufficient safety information to support the benefit–risk assessment of this IV regimen. A population pharmacokinetic (popPK) analysis was conducted on a pool of 15 PsA or axSpA clinical trials to identify 1.75 mg/kg IV secukinumab q4w (with or without a 6 mg/kg IV loading dose at Week 0) as a regimen with steady-state exposure within the ranges of the approved SC regimens. This entitled its efficacy and safety to be assessed by full extrapolation from those of the approved SC regimens. This extrapolation was substantiated by the use of exposure-response analyses to predict the efficacy and safety of the IV regimen. Based on those analyses, this IV secukinumab regimen, not tested in clinical trials, was approved by the FDA for the treatment of patients with PsA and axSpA.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"118 2","pages":"480-488"},"PeriodicalIF":5.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3716","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197772","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}