Cts-Clinical and Translational Science最新文献

{"title":"Exposure Matching Using Population Pharmacokinetic Modeling and Simulation to Support Rimegepant Dose Selection for Pediatric Patients With Migraine","authors":"Craig M. Comisar,&nbsp;Jim H. Hughes,&nbsp;Gary Mo,&nbsp;Rajinder Bhardwaj,&nbsp;Abhijeet Jakate,&nbsp;Chay Ngee Lim,&nbsp;Jing Liu","doi":"10.1111/cts.70360","DOIUrl":"10.1111/cts.70360","url":null,"abstract":"<p>Rimegepant is a small molecule calcitonin gene-related peptide receptor antagonist approved as a 75 mg orally disintegrating tablet for the acute treatment of migraine and the prevention of episodic migraine in adults. A population pharmacokinetic model for oral rimegepant was previously developed using data from 11 phase I studies in adults. This analysis updated the population pharmacokinetic model with data from one pediatric (20 participants) and two adult (74 participants) studies. The resultant population pharmacokinetic model was used to predict rimegepant exposure following single or every-other-day dosing in a virtual pediatric population generated using United States national growth charts. Exposure with rimegepant 75 mg orally disintegrating tablet was evaluated in simulated participants aged 6 to 17 years (1000 simulations/1-year age group), and exposure with rimegepant 25, 35, 50, and 75 mg was evaluated in simulated participants weighing 9 to 75 kg (1000 simulations/5 kg increment). Rimegepant doses for pediatric patients were selected using predicted pediatric/adult exposure ratios close to 1 and ≤ 2. The recommended single and every-other-day doses of rimegepant orally disintegrating tablet in the pediatric population were 75 mg in adolescents 12 to &lt; 18 years of age and children 6 to &lt; 12 years of age and with a body weight &gt; 40 kg; 50 mg in children 6 to &lt; 12 years of age with a body weight &gt; 25 to ≤ 40 kg; and 35 mg in children 6 to &lt; 12 years of age with a body weight &gt; 15 to ≤ 25 kg. These selected doses will support further evaluation of rimegepant efficacy and safety in pediatric patients with migraine.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of QT Interval Prolongation Using Concentration–QT Modeling for Iptacopan, an Oral Complement Factor B Inhibitor, in Healthy Individuals","authors":"Noemi Kaetterer,&nbsp;Kenneth Kulmatycki,&nbsp;Prasanna Kumar Nidamarthy,&nbsp;Elizabeth McNamara,&nbsp;Danielle Armas,&nbsp;Venkateswar Jarugula,&nbsp;Robert Schmouder","doi":"10.1111/cts.70361","DOIUrl":"10.1111/cts.70361","url":null,"abstract":"<p>To assess cardiac and safety parameters of iptacopan (an oral, selective, reversible, small-molecule factor B inhibitor), we conducted a phase I, single ascending dose (SAD), exposure–response study (A2107) instead of a traditional thorough QT study. Healthy participants were randomized 3:1 to receive a single, supratherapeutic, oral dose of iptacopan 400, 800, or 1200 mg, or placebo. A2107's primary objectives were to assess iptacopan's effect on Fridericia-corrected QT interval (QTcF) in a pooled analysis with the SAD phase of the first-in-human X2101 study, and the safety and tolerability of supratherapeutic iptacopan doses in participants. Secondary objectives included pharmacokinetics, changes in selected electrocardiogram (ECG) parameters, and categorical changes to the QTcF, PR, and QRS intervals and heart rate (pooled analysis). Thirty-two participants were randomized in A2107 and 56 in X2101; demographic data were similar across treatment groups. The estimated placebo-adjusted change from Day 1 baseline in QTcF at the geometric mean maximum drug concentration was 1.61 (90% confidence intervals: 0.39 to 2.82), 1.26 (−0.42 to 2.94), and 0.84 (−1.54 to 3.22) ms for 400, 800, and 1200 mg doses, respectively. These primary results are consistent with no risk of QT prolongation at single, supratherapeutic, oral iptacopan doses; secondary ECG data support this conclusion. No deaths, serious adverse events (AEs), or AEs leading to study discontinuation were reported; iptacopan was overall well tolerated. A high systemic exposure of iptacopan was confirmed, allowing us to conclude that single, supratherapeutic, oral doses of iptacopan had no QTcF prolongation or proarrhythmic potential in healthy individuals.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145287604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically Based Pharmacokinetic Modeling of Valemetostat to Inform Dose Recommendations When Coadministered With CYP3A/P-gp Modulators","authors":"Akiko Watanabe,&nbsp;Noriko Okudaira,&nbsp;Masaya Tachibana,&nbsp;Miho Kazui,&nbsp;Masakatsu Kotsuma,&nbsp;Takako Shimizu,&nbsp;Yvonne Lau","doi":"10.1111/cts.70333","DOIUrl":"10.1111/cts.70333","url":null,"abstract":"<p>Valemetostat tosylate (valemetostat) is an oral, potent, selective dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, approved in Japan for the treatment of relapsed/refractory adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma. Results from in vitro and clinical studies suggest that valemetostat is pre-systemically metabolized by cytochrome P450 3A (CYP3A) in the gut and excreted into bile and urine via P-glycoprotein (P-gp) in its unchanged form and as an oxidative metabolite. In this study, a physiologically based pharmacokinetic (PBPK) model was developed by utilizing available in vitro and clinical pharmacokinetics (PK) data to predict the impact of CYP3A and P-gp modulators on the PK of valemetostat. The developed PBPK model was validated against clinical drug–drug interaction studies with a moderate CYP3A inhibitor (fluconazole), a strong CYP3A/P-gp dual inhibitor (itraconazole), and a strong CYP3A/P-gp dual inducer (rifampicin), indicating that the contributions of CYP3A and P-gp in the gut and liver to valemetostat PK were appropriately described in the PBPK model. The validated model was applied to assess the effect of either a CYP3A or a P-gp inhibitor, or a moderate CYP3A inducer on valemetostat PK. The PBPK model incorporating the contribution of CYP3A and P-gp in the gut and liver effectively estimated the effect of CYP3A/P-gp modulators on valemetostat PK and can be used to inform dose recommendations for valemetostat upon coadministration with other treatments.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Metabolic Genotype Composite CYP3A5*3 and CYP3A4*1B to Tacrolimus Pharmacokinetics in Stable Black and White Kidney Transplant Recipients","authors":"Daniel Brazeau,&nbsp;Kristopher Attwood,&nbsp;Louse M. Cooper,&nbsp;Vanessa Gray,&nbsp;Shirley Chang,&nbsp;Shirley Chen,&nbsp;Brian M. Murray,&nbsp;Kathleen M. Tornatore","doi":"10.1111/cts.70370","DOIUrl":"10.1111/cts.70370","url":null,"abstract":"<p>Interpatient variability in tacrolimus pharmacokinetics is due in part to variation in metabolism by cytochrome P-450 3A5 and 3A4 and membrane transport by P-glycoprotein. We evaluated the combined role <i>CYP3A5*3</i> and <i>CYP3A4*1B</i> genotypes have on tacrolimus pharmacokinetics in 65 stable Black and White kidney transplant recipients receiving maintenance immunosuppression of tacrolimus and mycophenolic acid. Tacrolimus apparent clearance, trough (C_12h), C_12h/Dose, AUC_0–12, and AUC_0–12/Dose as well as <i>CYP3A5 *3</i> (rs776746) variants responsible for loss of protein function and <i>CYP3A4-1B</i> (<i>rs2740574</i>) associated with increased CYP3A4 function were assessed. To investigate the association of tacrolimus pharmacokinetics with the <i>CYP3A5 *3</i> and <i>CYP3A4*1B</i> genotypes, we created a metabolic composite to classify patients as Extensive, Intermediate, and Poor Metabolizers on the basis of the relative expression of specific combinations of <i>CYP3A5 *3</i> and <i>CYP3A4*1B</i> genotypes. The incorporation of <i>CYP3A5*3</i> and <i>CYP3A4*1B</i> genotypes that investigate the role of these composite genotypic variants on tacrolimus pharmacokinetics provides additional insights into targeted tacrolimus dosing regimens in these sub-populations. The Extensive Metabolic Composite had twice the dose and toughs when compared to the Poor composite. Approximately 88% of Blacks were classified as Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. The remaining Blacks exhibited loss of function SNPs associated with lower tacrolimus doses comparable to Whites. This is the first report describing the association of <i>CYP3A5*3 and CYP3A4-1B</i> Metabolic Composites on tacrolimus pharmacokinetics in Black and White kidney transplant recipients and provides insight into the interpatient pharmacokinetic variability of this key immunosuppressive drug.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Safety of Fixed-Dose Versus Separate Enavogliflozin/Gemigliptin Combinations, and Food Effect on Enavogliflozin in Healthy Korean Subjects","authors":"Young-Sim Choi,&nbsp;JAEJIN NA,&nbsp;Seo Yeong Park,&nbsp;Jae Min Cho,&nbsp;Yoonhye Jeong,&nbsp;Jun Gi Hwang","doi":"10.1111/cts.70376","DOIUrl":"10.1111/cts.70376","url":null,"abstract":"<p>Envlo (enavogliflozin) 0.3 mg, an SGLT2 inhibitor, was approved in Korea in 2022 for glycemic control in type 2 diabetes (T2DM). This study evaluates its safety, pharmacokinetics, and food effects. Healthy subjects (age ≥ 19, weight ≥ 50.0 kg, body mass index (BMI) 18.0–30.0 kg/m²) were enrolled. Study I was a randomized, two-way crossover study with an 8-day washout, where subjects received either a separate or a fixed-dose combination (FDC) of enavogliflozin 0.3 mg/gemigliptin 50 mg. Study II, a randomized, open-label, two-way crossover design with a 7-day washout, compared the food effect of a single dose of enavogliflozin in fed versus fasted after a high-fat meal. In study I, enavogliflozin reached peak plasma concentration at 1.25 h (median) in both groups. The mean half-life (<i>t</i>_1/2) was also comparable, recorded as 12.56 ± 4.04 h for the separate combination and 12.23 ± 3.46 h for the FDC. Gemigliptin peaked at 2.00 h in the separate combination and at 3.00 h in the FDC. The mean <i>t</i>_1/2 was 18.04 ± 1.75 h for the separate combination and 18.67 ± 2.54 h for the FDC. In study II, the plasma concentration of enavogliflozin 0.3 mg peaked at 1.25 and 2.00 h (median), indicating a delayed <i>T</i>_max in the fed group. The average <i>t</i>_1/2 was similar at 12.49 ± 2.12 h and 12.30 ± 2.81 h, respectively. The FDC of enavogliflozin and gemigliptin demonstrated pharmacokinetic equivalence and comparable safety to their co-administration as separate agents. Furthermore, the systemic exposure of enavogliflozin was not affected by food intake, supporting its potential for flexible, meal-independent use in clinical settings.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12518504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145287605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Characterization of Psychiatric Pharmacogenomic Test Ordering and Clinical Relevance in Adults and Children","authors":"Lusi Zhang,&nbsp;Anthony J. Tholkes,&nbsp;Kaliya C. Jones,&nbsp;Laylia J. Yang,&nbsp;Gretchen K. Sieger,&nbsp;Kathryn R. Cullen,&nbsp;Meredith L. Gunlicks-Stoessel,&nbsp;Pawel Mroz,&nbsp;Joel F. Farley,&nbsp;Steven G. Johnson,&nbsp;Jeffrey R. Bishop","doi":"10.1111/cts.70297","DOIUrl":"https://doi.org/10.1111/cts.70297","url":null,"abstract":"<p>Pharmacogenomic (PGx) testing is increasingly utilized to guide psychiatric medication selection and dosing, yet real-world characterizations of test ordering and clinical implications remain understudied. Additionally, the extent to which psychiatry-focused PGx results inform prescribing beyond mental health medications is unclear. This study examined patterns of psychiatry-focused PGx test ordering, the clinical relevance of results among adult and pediatric patients, and implementation challenges within a large health system. Electronic health records (EHRs) of 3383 individuals undergoing psychiatry-focused PGx testing between 2013 and 2023 were analyzed. Test reports, available as unstructured PDFs, required manual curation before merging with clinical data. Demographic characteristics, test ordering patterns, genotype distributions, and drug-gene interactions (DGIs) were assessed. Results indicated that 94.5% of individuals had one or more clinically actionable PGx variants. DGIs were identified for current psychiatric medications in 19.3% of adults and 15.0% of youth. Additionally, non-psychiatric DGIs were identified in 11.8% of adults and 2.1% of youth. Most patients had genotype profiles that could guide future psychiatric and non-psychiatric prescribing. Despite the clinical relevance, PGx results were inconsistently integrated into EHRs, limiting accessibility and reuse. Indicators of disparities in test ordering related to gender and race suggested systemic inequities and variability in provider adoption practices. Psychiatry-focused PGx testing holds substantial potential to optimize current and future medication prescribing, extending beyond psychiatry. Key challenges include fragmented EHR integration, inconsistent provider adoption, and disparities in test ordering. Improved standardized reporting, structured EHR integration, and enhanced provider education are necessary to maximize PGx benefits in patient care.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145272370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Cardiac Sodium Channel Safety Profile of Cenobamate at Therapeutic Concentrations: In Vitro Analyses","authors":"William J. Crumb Jr,&nbsp;Susan M. Melnick,&nbsp;Kelli J. Glenn","doi":"10.1111/cts.70378","DOIUrl":"10.1111/cts.70378","url":null,"abstract":"<p>The US Food and Drug Administration (FDA) issued a Drug Safety Communication for the antiseizure drug lamotrigine (Lamictal), warning of the risk of QRS prolongation and cardiac arrhythmias. The FDA also requested that other antiseizure medications with a similar mechanism of action (e.g., block of neuronal sodium channels), including cenobamate, be evaluated for their risk as a cardiac sodium channel blocker. The purpose of this in vitro study was to determine the cardiac sodium channel blocking effects of cenobamate and its sodium channel classification. Follow-up experiments were also performed with cenobamate at its highest free therapeutic concentration (66 μM). Experiments were performed using the manual patch clamp technique at physiologic temperatures. Despite its classification as a Class Ib and Id antiarrhythmic, cenobamate was found to have little effect on the cardiac sodium channel when tested in vitro at therapeutic levels. These findings provide further clarity and support for the clinical safety of cenobamate in patients without cardiovascular risk factors.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiolabelled Cyclodextrins for the Positron Emission Tomography Imaging of Breast Cancer: Preclinical Perspectives","authors":"Tamás Sass,&nbsp;Judit P. Szabó,&nbsp;Renáta Adél Dienes,&nbsp;Péter Árkosy,&nbsp;Gábor Opposits,&nbsp;István Jószai,&nbsp;Anikó Fekete,&nbsp;Ferenc Fenyvesi,&nbsp;István Hajdu,&nbsp;György Trencsényi,&nbsp;Zita Képes","doi":"10.1111/cts.70379","DOIUrl":"10.1111/cts.70379","url":null,"abstract":"<p>Given the increasing incidence and mortality of breast cancer, the development of target-specific imaging probes for early disease detection seems straightforward. Prostaglandin E2 (PGE2) and its receptors have a crucial role in tumor angiogenesis; therefore, radiolabelled cyclodextrins targeting such biomolecules may serve as selective vectors for positron emission tomography (PET) imaging of breast cancer. Herein, we aimed to monitor PGE2 production in MDA-MB-HER2-positive and 4 T1 triple-negative breast cancer xenografts using ⁶⁸Ga-labeled randomly methylated beta cyclodextrin (RAMEB) and 2-hydroxypropyl-beta-cyclodextrin (HPβCD) and PET technique. After the injection of [⁶⁸Ga]Ga-NODAGA-HPβCD and [⁶⁸Ga]Ga-DOTAGA-RAMEB, CB17 SCID mice bearing breast tumors underwent weekly PET imaging with subsequent quantitative data assessment and ex vivo biodistribution studies. Both cyclodextrin compounds were suitable to identify the tumors, though tracer accumulation varied with tumor size. Significantly higher [⁶⁸Ga]Ga-NODAGA-HPβCD uptake was observed in the MDA-MB-HER2+ tumors across all sizes (small, medium, and large-sized) compared to the 4 T1 counterparts. In contrast, [⁶⁸Ga]Ga-DOTAGA-RAMEB accumulated to a greater extent in small and midsized 4 T1 tumors in comparison with size-matched MDA-MB-HER2+ tumors, while it showed higher uptake in the large HER2+ lesions than in 4 T1. The presented results indicate notable radioactivity in both 4 T1 and MDA-MB-HER2+ tumors designating [⁶⁸Ga]Ga-DOTAGA-RAMEB and [⁶⁸Ga]Ga-NODAGA-HPβCD as effective PET probes for the identification of breast cancer.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive Analysis for First Submission of Generic Drug Application for Orphan Drug Products Using Random Survival Forest","authors":"Robert Hopefl,&nbsp;Jing Wang,&nbsp;Abhinav Ram Mohan,&nbsp;Wei-Jhe Sun,&nbsp;Myong-Jin Kim,&nbsp;Meng Hu,&nbsp;Lanyan Fang","doi":"10.1111/cts.70365","DOIUrl":"10.1111/cts.70365","url":null,"abstract":"<p>Rare diseases affect a small population of patients, resulting in low incentives for developing orphan drug products (ODPs). The United States Congress passed the Orphan Drug Act of 1983 to incentivize pharmaceutical manufacturers to develop drugs to treat rare diseases. However, ODPs generally have higher treatment costs than non-ODP treatments. Developing generic ODPs can benefit patients by increasing market competition and providing alternate treatment options. This research aims to identify factors influencing the first submission of abbreviated new drug applications (ANDAs) for generic orphan drugs. Data were collected from the U.S. Food and Drug Administration (FDA) databases (including but not limited to the FDA Orphan Drug Designations and Approvals database, Orange Book, and the internal drug product complexity designation) and the IQVIA sales database to inform the drug product information, regulatory factors, and pharmacoeconomic factors. The Random Survival Forest (RSF) machine learning method was employed to conduct the analysis for New Chemical Entities (NCEs) and non-NCEs. The modeling analysis was adequately assessed through both internal and external validations. For NCEs and non-NCEs, the RSF was able to predict ANDA submission with a repeated cross-validation C-index of 0.675 ± 0.0261 (C-index of full training dataset: 0.915) and 0.754 ± 0.0441 (C-index of full training dataset: 0.838), respectively. The variables with the highest importance in the RSF model to predict ANDA submission of NCE ODPs were sales data, while for non-NCEs, regulatory data was the most important (i.e., availability of product-specific guidances (PSGs)). As more data becomes available in the future, the RSF methodology will likely be able to predict ANDA submissions of ODPs more effectively. The model-informed results may be utilized in future intervention strategies to promote ANDA submissions for orphan drugs and to increase the availability of generic ODPs.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Higher Education Influences Stroop Performance in Non-Demented Older Adults: The Mediating Role of Resting-State Brain Activity","authors":"Zhiyuan Wang,&nbsp;Song Gao,&nbsp;Qiaoji Qin,&nbsp;Jianshuai Li,&nbsp;Jinchao Pang,&nbsp;Lei Wang,&nbsp;Jinping Sun","doi":"10.1111/cts.70372","DOIUrl":"10.1111/cts.70372","url":null,"abstract":"<p>Although extensive research has linked education to the Stroop effect, the neural mechanisms by which higher education influences Stroop performance in non-demented older adults remain unclear. This study investigated this relationship in 126 older adults from Qingdao, stratified into higher education (&gt; 12 years) and non-higher education (≤ 12 years) groups. Demographic data and Stroop performance were collected using a 50-item Stroop Color–Word Test (SCWT), yielding measures of completion time, correct responses, score-time ratio (efficiency), and time interference score (TI). Resting-state fMRI (rs-fMRI) was performed, and neural activity was assessed via amplitude of low-frequency fluctuations (ALFF) to identify regions of interest (ROIs). Multivariable regression models examined associations between education and Stroop outcomes, followed by correlation analyses between ROIs and performance. Bootstrap mediation analysis (5000 resamples) tested whether ROIs mediated the education–Stroop relationship. Results showed that higher education was significantly associated with better Stroop performance—shorter completion time, higher efficiency, and lower TI—after full adjustment (all <i>p</i> &lt; 0.05). Rs-fMRI revealed greater ALFF in the right frontal eye field (FEF), right dorsolateral prefrontal cortex (DLPFC), and left dorsal anterior cingulate cortex (dACC) in the higher education group. These regions correlated negatively with completion time and TI, and positively with efficiency. Mediation analyses confirmed that right FEF, right DLPFC, and the combined ROIs significantly mediated the effects of higher education on Stroop performance. In conclusion, higher education may enhance Stroop performance in non-demented older adults by modulating resting-state neural activity in key cognitive control regions.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}