Journal of Clinical Pharmacology最新文献_第3页

Can Methotrexate Monotherapy Achieve Clinical Remission in Patients with Active Rheumatoid Arthritis? A Model-Based Meta-Analysis. 甲氨蝶呤单药治疗活动性类风湿关节炎能否获得临床缓解？基于模型的元分析。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-06 DOI: 10.1002/jcph.70039

Shengyang Chen, Yangrui Wu, Wei Huang, Jianxing Zhou, Zipeng Wei, Xuemei Wu

{"title":"Can Methotrexate Monotherapy Achieve Clinical Remission in Patients with Active Rheumatoid Arthritis? A Model-Based Meta-Analysis.","authors":"Shengyang Chen, Yangrui Wu, Wei Huang, Jianxing Zhou, Zipeng Wei, Xuemei Wu","doi":"10.1002/jcph.70039","DOIUrl":"https://doi.org/10.1002/jcph.70039","url":null,"abstract":"This study utilized model-based meta-analysis (MBMA) to systematically assess the efficacy of methotrexate (MTX) monotherapy in improving rheumatoid arthritis (RA) symptoms and function. The assessment was based on indicators such as Disease Activity Score 28 (DAS28), Health Assessment Questionnaire, and American College of Rheumatology (ACR) criteria. Additionally, the study investigated the impact of dosage, disease duration, and serum markers-C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)-on treatment efficacy. A systematic review of randomized controlled trials yielded data from 69 studies involving 7999 patients. Efficacy models for DAS28, ACR20, and ACR50 were developed to explore the impact of time and dosage, with simulations conducted to predict outcomes at 12 weeks. Results showed that the maximum reduction in DAS28 (Emax) was -54.90% (RSE: 13%), with an ET50 of 20.6 weeks (RSE: 26%). For ACR20 and ACR50, Emax values were 70.3% (RSE: 3%) and 49.4% (RSE: 24%), with ET50s of 6.69 (RSE: 7%) and 27.3 (RSE: 37%) weeks, respectively. Neither dosage nor patient-specific factors like disease duration, CRP, or ESR significantly influenced efficacy. MTX is effective in the early treatment of RA but often fails to achieve remission in patients.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Systematic Evaluation of the Dosing Regimens for Approved Targeted Therapies and Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma From a Project OPTIMUS Perspective. 从OPTIMUS项目的角度对转移性肾细胞癌批准的靶向治疗和免疫检查点抑制剂的给药方案进行系统评估。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-02 DOI: 10.1002/jcph.70035

Zhiyuan Tan, Swantje Völler, Aymara Sancho-Araiz, Catherijne A J Knibbe, Dirk Jan A R Moes

{"title":"A Systematic Evaluation of the Dosing Regimens for Approved Targeted Therapies and Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma From a Project OPTIMUS Perspective.","authors":"Zhiyuan Tan, Swantje Völler, Aymara Sancho-Araiz, Catherijne A J Knibbe, Dirk Jan A R Moes","doi":"10.1002/jcph.70035","DOIUrl":"https://doi.org/10.1002/jcph.70035","url":null,"abstract":"Targeted therapies and immune checkpoint inhibitors (ICIs) have significantly improved survival outcomes in metastatic renal cell carcinoma (mRCC) but are often associated with high rates of adverse events, leading to dose reductions or treatment discontinuation. The FDA's recent initiative, Project OPTIMUS, emphasizes the importance of optimizing dosing regimens in oncology clinical development, and moves beyond the conventional maximum tolerated dose approach. In this study, we aimed to review and redefine the approved dosing strategies for targeted therapies and ICIs in mRCC from the Project OPTIMUS perspective, including pazopanib, axitinib, cabozantinib, sunitinib, everolimus, and nivolumab. A comprehensive summary of FDA clinical pharmacology reviews and clinical studies performed in routine clinical practice was conducted, alongside model-informed simulations of pharmacokinetic profiles with approved and alternative regimens. Results demonstrated that actual tolerated doses in clinical practice were 46.1% to 86% lower than the approved dosages, with up to 75% of patients requiring dose adjustments. Model-informed simulations suggested that for most targeted therapies, a 14%-50% dose reduction maintained comparable efficacy while improving tolerability. For nivolumab, simulations confirmed adequate drug exposure with the approved flat dose regimens, without an increase of adverse effects. In conclusion, we identified optimized dosing regimens that could improve drug tolerability while maintaining efficacy for approved targeted therapies and ICIs in mRCC. We suggest that these optimized dosing regimens should be considered for use in clinical practice and that the optimal exposure range be included in drug labels to support pharmacokinetically guided dose individualization in clinical practice.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Physiologically Based Modeling Approach to Evaluate Intravenous Levetiracetam Dosing in Term and Preterm Neonates. 一种基于生理学的建模方法来评估足月和早产儿静脉注射左乙拉西坦的剂量。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-05-02 DOI: 10.1002/jcph.70037

Alexis Johnson, Nolan Thomas, Max Blumenthal, Chrysanthy Ikonomidou, Sin Yin Lim

{"title":"A Physiologically Based Modeling Approach to Evaluate Intravenous Levetiracetam Dosing in Term and Preterm Neonates.","authors":"Alexis Johnson, Nolan Thomas, Max Blumenthal, Chrysanthy Ikonomidou, Sin Yin Lim","doi":"10.1002/jcph.70037","DOIUrl":"https://doi.org/10.1002/jcph.70037","url":null,"abstract":"Seizures are the most common neurologic emergency in neonates and are associated with significant morbidity and mortality. Current first-line pharmacotherapy, phenobarbital, is associated with serious adverse effects, including impairment of the developing brain. Levetiracetam is a well-tolerated alternative; however, its use is limited because its optimal dosing in neonates remains unknown. Additionally, limited knowledge of levetiracetam pharmacokinetics in neonates, especially preterm neonates, means they generally receive the same weight-based dosing. This may put preterm neonates at risk of increased adverse events or insufficient drug effects. This study developed a physiologically based pharmacokinetic (PBPK) model for levetiracetam in term and preterm neonates to evaluate their pharmacokinetic differences. After accounting for the physiological changes, a 1.56-fold increase in drug tissue distribution was needed to represent the increased volume of distribution of levetiracetam in neonates. In term neonates, scaling renal clearance from children based on estimated glomerular filtration rate required a 61% increase to accurately describe renal clearance. Additionally, allometric scaling to extrapolate metabolic clearance required age-dependent corrections to account for the reduced metabolic clearance. In preterm neonates, extrapolated renal clearance was approximately equal to observed total clearance, suggesting renal clearance as the sole elimination route. Consistently, predicted metabolic clearance approached zero when the postmenstrual age was <37.5 weeks. Our simulations showed that common intravenous levetiracetam dosing regimens resulted in higher plasma concentrations in more premature neonates or those with reduced kidney function. In preterm neonates, these regimens may result in plasma concentrations exceeding toxicity thresholds, indicating a need for lower weight-based dosing.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optimizing Zanubrutinib Dosing in Patients: A PBPK-BO Model Approach to Drug-Drug Interactions and Patients with Hepatic Impairment. 优化患者的扎鲁替尼剂量：药物-药物相互作用和肝功能损害患者的PBPK-BO模型方法。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-30 DOI: 10.1002/jcph.70042

Jiawei Ren, Dan Shan, Guijuan Yue, Qiang He

{"title":"Optimizing Zanubrutinib Dosing in Patients: A PBPK-BO Model Approach to Drug-Drug Interactions and Patients with Hepatic Impairment.","authors":"Jiawei Ren, Dan Shan, Guijuan Yue, Qiang He","doi":"10.1002/jcph.70042","DOIUrl":"https://doi.org/10.1002/jcph.70042","url":null,"abstract":"This study aimed to develop a physiologically based pharmacokinetic and Bruton's tyrosine kinase (BTK) occupancy (PBPK-BO) model to evaluate the pharmacokinetics (PK) and BTK occupancy (BO) of zanubrutinib (ZAN), particularly in relation to drug-drug interactions (DDIs) involving cytochrome P450 3A4 (CYP3A4) modulators and for patients with hepatic impairment. Population PBPK-BO and DDI models for ZAN were constructed using physicochemical properties, pharmacokinetic data, BTK occupancy levels, and physiological parameters. The PBPK-BO model was validated against clinically measured PK, DDI, and BO data, demonstrating accurate predictions of ZAN's plasma concentration and the time-course profiles of BO. The predicted ratios of AUC and Cmax in patients consistently fell within the acceptable range of 1.5-fold. The predicted fold-change ratios in DDIs and in patients with hepatic impairment also are in good agreement with the observed data. These findings confirm the reliability of the PBPK-BO model for predicting PK and BO of ZAN. Based on the model with >95% BO as a clinical efficacy threshold, the recommended dosing of ZAN should be reduced to 40 mg once daily (OD) when used with strong CYP3A4 inhibitors such as itraconazole or clarithromycin. For moderate CYP3A4 inhibitors like fluconazole, dosing should be adjusted to either 160 mg OD or 80 mg twice daily (BID). Additionally, the model advises against concomitant administration of ZAN with strong CYP3A4 inducers such as rifampicin or moderate inducers like rifabutin. Furthermore, the PBPK-BO model suggests that dosing regimens should be reduced to 80 mg BID or 160 mg OD in patients with severe hepatic impairment. The PBPK-BO model provides a robust framework for clinical decision-making, aimed at optimizing treatment outcomes in patients receiving ZAN therapy.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral Complement Factor D Inhibitor BCX9930 in Healthy Participants. 口服补体因子D抑制剂BCX9930在健康参与者中的安全性、耐受性、药代动力学和药效学的首次人体研究

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-28 DOI: 10.1002/jcph.70032

Matthew Davidson, Xilin Chen, Amanda Mathis, Sylvia Dobo, Melanie Cornpropst, Fugang Zhu, Cynthia Parker, David Reynolds, Yarlagadda S Babu, Stuart Mair, William P Sheridan

{"title":"First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral Complement Factor D Inhibitor BCX9930 in Healthy Participants.","authors":"Matthew Davidson, Xilin Chen, Amanda Mathis, Sylvia Dobo, Melanie Cornpropst, Fugang Zhu, Cynthia Parker, David Reynolds, Yarlagadda S Babu, Stuart Mair, William P Sheridan","doi":"10.1002/jcph.70032","DOIUrl":"https://doi.org/10.1002/jcph.70032","url":null,"abstract":"BCX9930 is a potent, selective oral inhibitor of complement Factor D that inhibits the activation of the complement alternative pathway (AP) and has the potential for treatment of complement-mediated diseases. This was a first-in-human, randomized, double-blind, placebo-controlled study that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BCX9930 in healthy participants. Safety and tolerability were evaluated via clinical and laboratory monitoring. Plasma concentrations of BCX9930 were measured using validated liquid chromatography-dual mass spectrometry; PD effects were assessed via multiple assays. Participants were enrolled into seven single dose cohorts (10-2000 mg) and eight multiple-dose cohorts (50-500 mg every 12 h [Q12h] and 1000-2000 mg every 24 h [Q24h]). Enrollment comprised 152 participants (122 received BCX9930 and 30 received placebo). Following BCX9930 administration, plasma exposure was approximately dose proportional across all doses. The effective half-life (t1/2) ranged from 6.45 to 7.75 h for Q12h doses at steady state. Clearance and times to maximum concentration (Tmax) were similar across all doses studied, without evidence of dose- or time-dependent clearance. BCX9930 administration resulted in rapid, potent, and dose-dependent AP inhibition. Doses ≥200 mg Q12h and ≥1000 mg Q24h achieved maximal suppression (>98% relative to baseline levels) of AP activity over the full dosing interval. No clinically significant dose-related trends in adverse events (AEs), laboratory values, vital signs, or electrocardiograms were noted. BCX9930 was safe and generally well tolerated in this first-in-human study and displayed highly favorable PK and PD profiles. These results support Factor D inhibition as a promising strategy for treatment of complement-mediated diseases.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity. 扩展地西泮的药代动力学模型，以表征患有和非肥胖儿童的静脉注射和口服数据。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-28 DOI: 10.1002/jcph.70027

Sean M McCann, Jiali Wen, Stephen J Balevic, William J Muller, Amira Al-Uzri, Chi D Hornik, Marisa L Meyer, Sarah G Anderson, Elizabeth H Payne, Sitora Turdalieva, James M Chamberlain, Daniel Gonzalez

{"title":"Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity.","authors":"Sean M McCann, Jiali Wen, Stephen J Balevic, William J Muller, Amira Al-Uzri, Chi D Hornik, Marisa L Meyer, Sarah G Anderson, Elizabeth H Payne, Sitora Turdalieva, James M Chamberlain, Daniel Gonzalez","doi":"10.1002/jcph.70027","DOIUrl":"https://doi.org/10.1002/jcph.70027","url":null,"abstract":"Diazepam is a benzodiazepine approved for use in adults and children. The label incorporates recommended dosing for status epilepticus in children. Published population pharmacokinetic (PK) modeling recommends an intravenous bolus dose of 0.2 mg/kg capped at 8 mg to reach the suggested target exposure of 200-600 ng/mL at 10 min post dose in children up to 17 years of age. This model was developed for children generally without obesity based on IV data, and it is unclear how increased body weight may affect exposure or target attainment given capped dosing. Diazepam concentrations after IV or oral administration for 61 children aged 2.5 to 20.6 years were used to externally evaluate the model including the addition of fixed oral absorption parameters. Then, PK parameters were re-estimated with the external population alone and again in combination with the original population. Re-estimated parameters from the combined population were used to simulate recommended dosing for children with and without obesity. The external dataset included 88 plasma concentrations from 61 children (54 with obesity) receiving diazepam per standard of care. The external evaluation resulted in 34.5% of predicted values within 30% of the observed concentration. Parameter re-estimation resulted in increased central volume of distribution (26% increase from a previous model), reduced peripheral volume of distribution and intercompartmental clearance, and similar clearance estimates. Simulations demonstrated that dosing caps may prevent children with obesity from reaching the suggested target exposure that is recommended for the treatment of status epilepticus. Further study is needed to evaluate the target exposure range in this population.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

How to Peer Review a Systematic Review: A Peer-Reviewer's Guide to Reviewing Reviews. 如何同行评审系统评审：同行评审评审指南。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-23 DOI: 10.1002/jcph.70036

Luke Baxter

{"title":"How to Peer Review a Systematic Review: A Peer-Reviewer's Guide to Reviewing Reviews.","authors":"Luke Baxter","doi":"10.1002/jcph.70036","DOIUrl":"https://doi.org/10.1002/jcph.70036","url":null,"abstract":"Systematic reviews hold significant academic weight, but poor execution can render them misleading and unreliable. To help improve the quality of systematic reviews, the peer review process plays a crucial role. Peer reviewing systematic reviews requires a distinct skill set compared to reviewing primary research studies. Systematic reviews differ in their methodology and reporting standards, necessitating a structured approach to evaluation. This commentary offers guidance on best practice when peer reviewing systematic reviews, with an emphasis on synthesis of quantitative data from clinical trials. In this article, nine key topics are covered, namely correct classification of review type, adherence to systematic methods, pre-registration, methodological and reporting quality, search strategy evaluation, risk of bias assessment, evidence synthesis methods, data and code availability, and use of standardized assessment tools. By helping to ensure best practice is followed for each of these topics, peer reviewers can play a crucial role in upholding the methodological integrity of systematic reviews, ensuring they contribute reliable and meaningful evidence to the scientific literature.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Crowdsourcing Proposal Supporting Patient Engagement in Parkinson's Disease: A Digital Research Environment (DRE)-Enabled, Patient Swarm Approach to Develop QSP Models. 支持帕金森病患者参与的众包建议：数字研究环境（DRE）支持的患者群体方法开发QSP模型。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-22 DOI: 10.1002/jcph.70028

Jeffrey S Barrett, Benedetto Piccoli, Christopher Denaro, Stephan Schmidt, Valvanera Vozmediano, Serge Guzy, Kyle Barrett, Kevin Kwok, Scott Russell, David Sibbald

{"title":"Crowdsourcing Proposal Supporting Patient Engagement in Parkinson's Disease: A Digital Research Environment (DRE)-Enabled, Patient Swarm Approach to Develop QSP Models.","authors":"Jeffrey S Barrett, Benedetto Piccoli, Christopher Denaro, Stephan Schmidt, Valvanera Vozmediano, Serge Guzy, Kyle Barrett, Kevin Kwok, Scott Russell, David Sibbald","doi":"10.1002/jcph.70028","DOIUrl":"https://doi.org/10.1002/jcph.70028","url":null,"abstract":"Seeking to incorporate the patient voice into a collaborative effort to develop a quantitative system pharmacology (QSP) model for Parkinson's disease (PD) we propose the creation of a \"patient swarm\" in conjunction with a digital research environment (DRE) connecting various academic centers of excellence and their compute environments to promote data sharing and model collaboration with patient engagement. Patients, their advocates, and other stakeholders are welcome to join the crowdsourcing effort with the intention of reading the relevant source literature and contributing thoughts on model priors and model development while sharing their personal disease trajectories. Training materials are provided from experienced modelers and clinical stakeholders and maintained on the DRE as a resource for the \"Swarm.\" While a number of prominent modelers and clinical stakeholders are part of the initial effort to date, there is an open invitation to the global PD research community to join this effort and help contribute to a solution.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Trends in First-in-Human Studies for Intrathecal Antisense Oligonucleotides: Insights From 2010 to 2024. 鞘内反义寡核苷酸首次人体研究的趋势：从2010年到2024年的见解。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-20 DOI: 10.1002/jcph.70034

Natalie Schmitz, Mai M Abdelmageed, Michael Monine, Yan Xu

{"title":"Trends in First-in-Human Studies for Intrathecal Antisense Oligonucleotides: Insights From 2010 to 2024.","authors":"Natalie Schmitz, Mai M Abdelmageed, Michael Monine, Yan Xu","doi":"10.1002/jcph.70034","DOIUrl":"https://doi.org/10.1002/jcph.70034","url":null,"abstract":"Advancements in antisense oligonucleotide (ASO) therapies have expanded their application to neurological disorders through intrathecal (ASO-IT) delivery into cerebrospinal fluid (CSF). To examine study designs and practices in ASO-IT first-in-human (FIH) trials, we analyzed 29 trials between 2010 and 2024 via a comprehensive review. Most trials targeted rare neurological disorders, with increasing numbers of ASO-ITs advancing to clinical testing over time. Patient populations were predominantly used over healthy participants, with over 50% trials employing randomized controlled designs (3:1 active-to-placebo) while others were open label. Trials commonly start in adults or older children before expanding to younger cohorts. Recent trends reveal increased uses of direct-to-multiple ascending dose strategies and single-patient trials, particularly for rare diseases. Dose escalations typically spanned four cohorts over a 10× dose range, with early escalations up to 4× between adjacent cohorts and smaller increments (1.25-1.5×) in later cohorts. Human dose selection often integrates translational modeling and human equivalent dose approach, scaled by CSF or central nervous system (CNS) tissue volumes. Starting doses prioritized robust safety margins (median 30×) with limited pharmacological activity, while top doses aimed therapeutic benefit with high activity and safety margins ≥1×, with the goal to achieve ≥70%-80% target engagement (e.g., mRNA knockdown) during dose escalation. Dosing intervals, typically 2-4 weeks (up to 12 weeks), reflected ASO-ITs' prolonged CNS half-life. Adaptive designs enabled real-time dose adjustments upon emerging safety and pharmacokinetics/pharmacodynamic data. This analysis highlights the importance of flexible, personalized, innovative FIH designs, such as single-patient studies, and model-informed strategies to advance ASO-IT development for rare neurological diseases.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Retrospective Analysis of PK and Response of Oral Ibuprofen in the Treatment of a Patent Ductus Arteriosus in Extremely Low Gestational Age Neonates. 口服布洛芬治疗极低胎龄新生儿动脉导管未闭的PK和疗效回顾性分析。

IF 2.9 4区医学

Journal of Clinical Pharmacology Pub Date : 2025-04-16 DOI: 10.1002/jcph.70033

Mohd Asif, Katelyn Sushko, Abdul Razak, Sayem Borhan, Michael Rieder, John van den Anker, Samira Samiee-Zafarghandy

{"title":"A Retrospective Analysis of PK and Response of Oral Ibuprofen in the Treatment of a Patent Ductus Arteriosus in Extremely Low Gestational Age Neonates.","authors":"Mohd Asif, Katelyn Sushko, Abdul Razak, Sayem Borhan, Michael Rieder, John van den Anker, Samira Samiee-Zafarghandy","doi":"10.1002/jcph.70033","DOIUrl":"https://doi.org/10.1002/jcph.70033","url":null,"abstract":"Oral ibuprofen is the preferred pharmacotherapeutic option for treatment of a persistent patent ductus arteriosus (PDA), but evidence for its optimal use in extremely low gestational age newborns (ELGANs) remains limited. In the current study, we aimed to investigate the pharmacokinetics and exposure-response relationship of oral ibuprofen in ELGANs of ≤72 h postnatal age (PNA) on standard (SD) versus those >72 h PNA on high-dose (HD) regimen for closure of persistent PDA. This was a retrospective analysis of data from a previous population PK study of ELGANs with a persistent PDA treated with a SD (10-5-5 mg/kg/day, PNA <72 h) versus a HD (20-10-10 mg/kg/day, PNA >72 h) oral ibuprofen, with the primary aim of comparing degree of exposure, defined as AUC0-24 (AUC from time 0 to 24 h). Twelve ELGANs received SD versus 11 receiving HD oral ibuprofen. The mean (SD) of exposure at 24 h (AUC0-24 h) was 486 (128) and 509 (208) (P = .41) and at 72 h (AUC0-72 h) was 1529 (493) and 1510 (820) (P = .94). Two (16%) ELGANs in the HD group developed severe gastrointestinal (GI) AEs and 1 (9%) in the SD had severe intraventricular hemorrhage. The use of SD and HD oral ibuprofen in ELGANs with PNA of <72 h and those >72 h, respectively, resulted in comparable exposure. The PNA-dependent response to oral ibuprofen and exposure-response relationship in ELGANs of higher PNA needs further investigation.","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0