The Journal of Clinical Pharmacology最新文献

{"title":"Clinical Pharmacology of Eplontersen, the First Approved GalNAc-Conjugated Antisense Oligonucleotide","authors":"Rosie Z. Yu PhD,&nbsp;John K. Diep PharmD,&nbsp;Xiang Gao PhD,&nbsp;Cecilia Arfvidsson PhD,&nbsp;Angelica Quartino PhD","doi":"10.1002/jcph.70276","DOIUrl":"10.1002/jcph.70276","url":null,"abstract":"<p>Eplontersen is a GalNAc-conjugated antisense oligonucleotide (ASO) approved for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). GalNAc conjugation enables targeted hepatic delivery and improved potency compared with unconjugated ASOs. The clinical pharmacology of eplontersen was characterized by using in vitro studies and data from three Phase 1 studies in healthy participants and one pivotal Phase 3 study in patients with ATTRv-PN. Following subcutaneous administration, eplontersen was rapidly absorbed and exhibited a biphasic pharmacokinetic (PK) profile with a terminal half-life of approximately 3 weeks, supporting once-monthly dosing. Eplontersen is highly plasma protein‑bound, distributes predominantly within the plasma compartment before receptor‑mediated tissue uptake, and is eliminated mainly via nuclease‑mediated metabolism, with minimal renal excretion of intact drug. Across integrated population PK/PKPD and exposure–response analyses at 45 mg Q4W, eplontersen exhibits predictable PK, robust PD, exposure-independent efficacy within the achieved range, and no exposure-dependent safety signals. Albeit some covariates were identified as statistically significant for population PK and population PKPD models, they were not considered clinically meaningful when taking into account the overall variability in PK, their minimal impact on TTR reduction, and the therapeutic window for eplontersen. These findings support that 45 mg Q4W is appropriate for patients with ATTRv-PN without the need for dose modification. In vitro and model-based analyses indicate low potential for clinically relevant plasma protein binding displacement and CYP- or transporter-mediated drug–drug interactions, and demonstrate no clinically meaningful effects on the QT prolongation and a predominantly non-neutralizing anti-drug antibody profile without impact on efficacy or safety.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-In-Human Evaluation of the Pharmacokinetics, Pharmacodynamics, and Safety of Tilpisertib Fosmecarbil (GS-5290), an Oral Prodrug of a Tumor Progression Locus 2 Inhibitor in Healthy Participants","authors":"Priyanka A. Madia PhD,&nbsp;Emily R. Wendt PhD,&nbsp;Ann Ran-Ran Qin MSc, MBA,&nbsp;Xin Qi PhD,&nbsp;Yan Liang PhD,&nbsp;Shital Kalariya MD,&nbsp;Frank Hong MD, PhD,&nbsp;Eda Canales PhD,&nbsp;James G. Taylor PhD,&nbsp;Udayasankar Arulmani MD, Msc, PhD,&nbsp;Tarundeep Kakkar PhD","doi":"10.1002/jcph.70269","DOIUrl":"10.1002/jcph.70269","url":null,"abstract":"<p>Tilpisertib fosmecarbil (TIP; GS-5290) is an intestinally cleaved prodrug of GS-4875, a potent tumor progression locus 2 (TPL2) inhibitor being investigated for ulcerative colitis (UC). The pharmacokinetics, pharmacodynamics, and safety of single or multiple (over 10 days) oral doses of TIP (N = 73; 75-1500 mg) or GS-4875 (N = 82; 15-450 mg) were assessed in two randomized, placebo-controlled studies in healthy participants. A third study (N = 32) assessed the renal effects of GS-4875 (300 mg daily) due to observed serum creatinine increases. TIP was generally undetectable in plasma after administration, indicating rapid conversion to GS-4875. GS-4875 had a half-life of 19-29 h after TIP administration and exposure was greater than with mg-equivalent doses of GS-4875 (population mean [90% CI] AUC_tau slope: 0.72 [0.59-0.85] versus 0.57 [0.47-0.67]). Inhibition of lipopolysaccharide-stimulated phosphorylated extracellular signal-regulated kinase (a TPL2 pathway pharmacodynamic biomarker) 24 h post last dose was greater with TIP versus GS-4875 dosing (&gt;90% [TIP 300-900 mg] versus 75-80% [GS-4875 450 mg]). Investigator-assessed, study drug-related adverse events (AEs) occurred in 9.3% (5/54) of TIP recipients and 5.3% (1/19) of placebo recipients (all grade 1 severity). No serious AEs or deaths occurred. GS-4875 and TIP reduced creatinine-based estimated glomerular filtration rate (GFR; day 10 baseline-adjusted geometric least-squares means ratio [90% CI] for GS-4875/placebo: 83.3% [79.2-87.5%]); this was attributed to renal transporter inhibition rather than GFR impairment as cystatin C- and iohexol-based GFR were unchanged. These data support further development of TIP in an ongoing phase 2 trial in UC (NCT06029972).</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Model-Informed Approaches in Neuroscience Drug Development and Regulatory Decision-Making","authors":"Michael Bewernitz PhD,&nbsp;Anantha Ram Nookala PhD,&nbsp;Gopichand Gottipati PhD FCP,&nbsp;Praveen Balimane PhD,&nbsp;Venkateswaran C. Pillai PhD,&nbsp;Jeffry Florian PhD,&nbsp;Adarsh Gandhi PhD,&nbsp;Kevin Krudys PhD,&nbsp;David Lee PhD,&nbsp;Dawei Li PhD,&nbsp;Min Li PhD,&nbsp;Zhihua Li PhD,&nbsp;Jie Liu PhD,&nbsp;Rajanikanth Madabushi PhD,&nbsp;Grimstein Manuela PhD,&nbsp;Mehul Mehta PhD,&nbsp;Srikanth C. Nallani PhD,&nbsp;Nimishraj Panse PhD,&nbsp;Wei Qiu PhD,&nbsp;Sreedharan Sabarinath PhD FCP,&nbsp;Vishnu Sharma PhD,&nbsp;Li Tan PhD,&nbsp;Ramana Uppoor PhD,&nbsp;Yun Xu PhD,&nbsp;Hao Zhu PhD,&nbsp;Venkatesh Atul Bhattaram PhD","doi":"10.1002/jcph.70272","DOIUrl":"10.1002/jcph.70272","url":null,"abstract":"<p>Model-informed drug development (MIDD) approaches are being increasingly used in neuroscience drug development programs and regulatory decision-making. In this work, the authors summarize a select set of cases in neurology, psychiatry, addiction, anesthesia, and analgesia, where MIDD approaches were utilized to address critical drug development questions or fill knowledge gaps. These examples include efficacy considerations such as biomarker-clinical endpoint relationships, surrogate endpoints for accelerated approval, extrapolation of efficacy, and safety aspects such as informing driving studies. Additionally, the examples also inform optimal dosing regimen selection, dose adjustments in drug interactions, life cycle management decisions such as indication expansion, formulation switching, and informing patient population selection. Together, these examples offer insights into the utility of MIDD approaches to streamline drug development and opportunities to save costs and resources.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Review of Semi-Mechanistic HbA1c Models in People with Type 2 Diabetes: Strengths, Limitations, and Applications","authors":"Austin Yue Feng Tan BSc,&nbsp;Parag Garhyan PhD,&nbsp;Lai San Tham PharmD","doi":"10.1002/jcph.70274","DOIUrl":"https://doi.org/10.1002/jcph.70274","url":null,"abstract":"<p>Type 2 diabetes (T2D) is a chronic metabolic disorder associated with high morbidity and mortality, necessitating the urgent need for the research of novel antidiabetic compounds. Population pharmacokinetic/pharmacodynamic (PK/PD) models have been used in T2D drug development to inform dose selection for antidiabetic compounds. However, most population PK/PD models are empirical, and physiological processes (e.g., glucose-mediated hemoglobin glycation) are not routinely incorporated. Conversely, semi-mechanistic models in people with T2D incorporate some relevant physiological processes, enabling prediction of long-term glycated hemoglobin (HbA1c) using only short-term glucose and HbA1c data. Semi-mechanistic T2D models may also have improved ability for extrapolation to multiple antidiabetic drug classes. This narrative review summarizes six published semi-mechanistic models commonly used or discussed for HbA1c prediction in people with T2D: A Dynamic HbA1c EndpOint Prediction Tool (ADOPT), FPG-FSI-HbA1c (FFH), FPG-Hb-HbA1c (FHH), Integrated Glucose-RBC-HbA1c (IGRH), Weight-HbA1c-Insulin-Glucose (WHIG), and Body Weight-Directed Disease Trial (BWDDT) models. An overview of the HbA1c predictive performance is presented for four of these models (ADOPT, FFH, FHH, and IGRH models). Strengths and limitations of the six semi-mechanistic T2D models are evaluated based on model assumptions, HbA1c model predictive performance, predictive accuracy for collected biomarker data, model complexity, and computational considerations. A decision tree framework is provided for model selection. Practical strategies for model development are discussed, including approaches for incorporating different drug effects into the models. Future directions include model validation with early-phase data from various antidiabetic drug classes, and exploration of alternative implementation of disease progression models.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PBPK Models for Fetal Drug Exposure: A Critical Assessment of Current Approaches and Regulatory Readiness","authors":"André Dallmann PhD,&nbsp;Andrew Butler PhD,&nbsp;Sophie Fischer-Holzhausen PhD,&nbsp;Essam Kerwash PhD,&nbsp;Julia Macente PhD,&nbsp;Nina Nauwelaerts PhD,&nbsp;Sílvia M. Illamola PharmD, PhD,&nbsp;Karen Rowland Yeo PhD,&nbsp;Jane Knöchel PhD","doi":"10.1002/jcph.70271","DOIUrl":"https://doi.org/10.1002/jcph.70271","url":null,"abstract":"<p>Physiologically based pharmacokinetic (PBPK) modeling has emerged as a critical tool for predicting fetal drug exposure during pregnancy, accounting for the complex interplay of maternal physiological changes and placental transfer mechanisms. This review summarizes the current state of PBPK modeling in maternal-fetal pharmacology, discussing various modeling approaches, including compartmental structures and mathematical formulations for placental transfer, as well as approaches to parameterize placental drug transfer in humans. Furthermore, a regulatory perspective on the use of maternal-fetal PBPK models in submissions to the MHRA is provided. Despite advancements, significant gaps remain in understanding the variability of placental drug transfer across gestational stages and the implications of transporter activity. Future research should focus on generating robust clinical data and integrating innovative technologies, such as organ-on-a-chip systems, to enhance model accuracy. Additionally, regulatory acceptance of PBPK models will depend on the establishment of comprehensive validation frameworks. By fostering collaboration between researchers, clinicians, and regulatory bodies, PBPK modeling can advance toward safer therapeutic options for pregnant women and their developing fetuses, ultimately improving maternal-fetal health outcomes.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-Informed Decision Making from Drug Discovery to Reimbursement: A Roadmap for Clinical Pharmacology in Value-Based Healthcare","authors":"Rajesh Krishna PhD,&nbsp;Ananth Kadambi PhD,&nbsp;Patrick Smith PhD,&nbsp;Piet H. van der Graaf PharmD, PhD,&nbsp;Fran Brown PhD","doi":"10.1002/jcph.70270","DOIUrl":"https://doi.org/10.1002/jcph.70270","url":null,"abstract":"<p>The transition to value-based healthcare demands more efficient, evidence-driven approaches to drug discovery, development and medical use. Clinical pharmacology is uniquely positioned to support this shift through model-informed drug development (MIDD) decision-making, integrating quantitative methods across the product lifecycle. This commentary outlines a roadmap for embedding MIDD from early drug discovery through regulatory evaluation and ultimately into reimbursement and real-world use. We highlight how pharmacokinetic/pharmacodynamic modeling, mechanistic modeling, disease progression models, patient-relevant endpoints, and real-world data will inform dose selection, optimize trial design, and reduce uncertainty in benefit–risk and cost-effectiveness assessments. Emphasis is placed on cross-stakeholder alignment, including regulators, payers, clinicians, and industry, to ensure that model-informed evidence translates into demonstrable patient and economic value. Key challenges, such as data integration, model transparency, and acceptance by decision-makers, are discussed alongside practical solutions. By advancing a lifecycle-based, quantitatively informed framework, clinical pharmacology can play a central role in delivering therapies that are not only safe and effective but also aligned with the principles of value-based healthcare.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70270","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide-Induced Nonarteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis","authors":"Elnaz Khani PharmD,,&nbsp;Hila Asham PharmD,,&nbsp;Aysa Rezabakhsh PhD,&nbsp;Shima Babaei PharmD,&nbsp;Taher Entezari-Maleki PharmD, PhD","doi":"10.1002/jcph.70248","DOIUrl":"https://doi.org/10.1002/jcph.70248","url":null,"abstract":"<p>Despite the recent reports of the potential association between semaglutide and nonarteritic anterior ischemic optic neuropathy (NAION), available evidence remains inconclusive. We aimed to evaluate the relative effect (RE) of NAION in individuals treated with semaglutide compared to the control group. The results of this systematic review and meta-analysis were reported according to the PRISMA guidelines. The study protocol was prospectively registered in PROSPERO with ID: CRD42025649542. A systematic search was performed on the PubMed, Embase, and Cochrane Library databases until May 18, 2026. Meta-analysis of REs with 95% confidence intervals (CI) was calculated using random-effects models. Eight observational cohort studies, involving a total of 5,916,559 participants, were included in the meta-analysis. Of these, 1,870,346 patients received semaglutide treatment, while 4,046,213 were administered non-semaglutide treatment. Compared to non-semaglutide-treated patients, semaglutide users had a higher risk of NAION (RE, 1.93; 95% CI, 1.22–3.08; I², 91%; <i>P</i>  =  .01). There was a significant association between NAION risk and semaglutide use in individuals with diabetes (RE, 1.84; 95% CI, 1.21–2.80; I², 88.26%; <i>P</i>  &lt; .01). However, the results were non-significant among overweight or obese individuals (RE, 1.68; 95% CI, 0.72–3.91; I², 83.98%; <i>P</i>  =  .23). The current meta-analysis suggests a possible association between semaglutide and risk of NAION. Further randomized clinical trials are required to draw a clear conclusion.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacology in China: Seven Decades of Progress in Discipline Development and Education","authors":"Guo-Xiang Hao PhD,&nbsp;Yue Zhou PhD,&nbsp;Bo-Hao Tang PhD,&nbsp;Hua-Jun Zhao PhD,&nbsp;Wei Wei PhD,&nbsp;John van den Anker MD, PhD,&nbsp;Wei Zhao PharmD, PhD","doi":"10.1002/jcph.70262","DOIUrl":"https://doi.org/10.1002/jcph.70262","url":null,"abstract":"<p>Clinical pharmacology serves as the central discipline supporting rational clinical medication, innovative drug research, and full-lifecycle pharmaceutical supervision. Domestic clinical pharmacology research began in the 1950s, and the field entered a period of rapid development after 1979 across three phases. This study sorts domestic disciplinary milestones and analyzes three key datasets: among the 1949 registered drug clinical trial institutions nationwide, nearly 50% are located in East China; investigational new drug applications surged from 446 (2012) to 3516 (2025); and the Center for Drug Evaluation issued 631 technical guidelines. The National Natural Science Foundation set up an independent clinical pharmacology discipline classification in 2015. The multi-tiered educational system is further elaborated: the transitional 5-year pharmacy (clinical pharmacology direction) track, standardized 5-year clinical pharmacy undergraduate programs, and clinical pharmacology-oriented postgraduate research sub-disciplines under pharmacy-related majors. Although the field has built a complete framework covering basic research, clinical practice and regulatory evaluation, critical bottlenecks persist. Clinical pharmacology is not listed as an independent major in national undergraduate and postgraduate catalogues, resulting in uneven educational standards, insufficient industry–academia integration, and striking regional gaps in disciplinary resources between eastern and inland areas. China's transitional undergraduate training model and phased regulatory improvements provide practical references for pharmaceutical regulators and educators worldwide. Targeted optimization strategies are proposed to construct unified tiered educational systems, deepen cross-stakeholder collaborative innovation, and balance regional disciplinary layouts. The sound and balanced development of clinical pharmacology will continuously advance standardized clinical medication, accelerate domestic new drug innovations, and strengthen national public health protection.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, Pharmacokinetics, Food effect, and Pharmacodynamics of AJM347, a Selective α4β7 Integrin Antagonist: A First-in-Human Single- and Multiple-Ascending Dose Study in Healthy Male Volunteers","authors":"Tetsuya Koyama MS,&nbsp;Tatsunori Seki BSc","doi":"10.1002/jcph.70260","DOIUrl":"https://doi.org/10.1002/jcph.70260","url":null,"abstract":"<p>This first-in-human study evaluated the safety, pharmacokinetics (PK), food effect, and pharmacodynamics (PD) of AJM347, a novel orally active, selective α4β7 integrin antagonist, in healthy Caucasian and Japanese adult males. The study consisted of three parts. In the single-ascending dose (SAD) study (Part 1), AJM347 was administered in doses ranging from 6 to 2420 mg. The effect of food was evaluated in Part 2. In the multiple-ascending dose (MAD) study (Part 3), AJM347 was administered twice daily (200–800 mg) for 7 days. Single and multiple oral doses of AJM347 were safe and well tolerated. No changes in lymphocyte counts in whole blood and cerebrospinal fluid were observed. AJM347 was rapidly absorbed and the active metabolite, CAN2281, was rapidly formed. Administration of AJM347 after meals achieved higher trough concentrations of CAN2281 compared with administration under fasted conditions. AJM347 rapidly and dose-dependently inhibited mucosal addressin cell adhesion molecule-1 binding to CD4+ T cells. Doses ≥200 mg twice daily maintained &gt;90% inhibition (α4β7 receptor occupancy) for up to 24 h. PD effects correlated well with plasma concentrations of the active metabolite CAN2281. AJM347 demonstrated a favorable safety profile, effective target engagement, and promising PK properties for oral administration. The timing of dosing relative to meals did not affect the safety or overall PK profiles, but postprandial administration led to higher trough concentrations, suggesting that dosing after meals may represent the optimal regimen for the continued clinical development of AJM347. Blood samples were collected to assess PK and PD (α4β7 receptor occupancy). Samples were also collected to measure lymphocyte counts in peripheral blood and cerebrospinal fluid (CSF).</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70260","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factor XI Inhibition for Ischemic Stroke Secondary Prevention: Pharmacology, Clinical Evidence, and Future Directions","authors":"Federica Ferrari MD, MSc, PhD, FCP,&nbsp;Roberto Federico Villa MD, MSc, FRSM","doi":"10.1002/jcph.70266","DOIUrl":"https://doi.org/10.1002/jcph.70266","url":null,"abstract":"<p>Ischemic stroke remains a leading cause of death and disability worldwide, and bleeding (particularly intracranial hemorrhage) continues to limit conventional antithrombotic therapy in secondary prevention, even with direct oral anticoagulants. Factor XI (FXI) has emerged as a promising target: it amplifies thrombin generation and stabilizes pathological thrombi while contributing only marginally to physiological hemostasis, as illustrated by the mild bleeding phenotype of congenital FXI deficiency. This biological dissociation underpins the concept of hemostasis-sparing anticoagulation. Three pharmacological classes are being studied, with distinct pharmacokinetic, pharmacodynamic, and drug-drug interaction profiles: small-molecule oral FXIa inhibitors (asundexian and milvexian), FXI antisense oligonucleotides (fesomersen), and monoclonal antibodies targeting FXI/FXIa (abelacimab and osocimab). Oral small molecules offer rapid, reversible target engagement particularly suited to chronic cerebrovascular prevention. While phase II trials (PACIFIC-Stroke, AXIOMATIC-SSP) showed neutral primary endpoints with reassuring safety, the phase III OCEANIC-STROKE trial demonstrated that asundexian 50 mg once daily, added to antiplatelet therapy, reduced recurrent ischemic stroke by 26% (HR 0.74; 95% CI 0.65–0.84) without significant bleeding excess in non-cardioembolic stroke; the ongoing LIBREXIA-STROKE is testing milvexian 25 mg twice daily in a similar setting. Conversely, OCEANIC-AF showed that FXIa inhibition alone is insufficient versus apixaban in atrial fibrillation, indicating dependence upon clinical setting and suggesting the need for a precision-medicine approach integrating clinical, imaging, and biomarker-based patient stratification. This narrative review integrates pathophysiological rationale, comparative pharmacology of all FXI-targeting classes, trial evidence, and patient stratification, providing an up-to-date reference for FXI/FXIa inhibition in secondary ischemic stroke prevention.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70266","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}