Cts-Clinical and Translational Science最新文献

{"title":"Application of Machine Learning for Predicting Progression-Free and Overall Survival in Patients With Renal Cell Carcinoma.","authors":"Caroline W Grant, Jerry Li, Swan Lin, Dana Nickens, Daniele Ouellet, Mohamed H Shahin","doi":"10.1111/cts.70348","DOIUrl":"https://doi.org/10.1111/cts.70348","url":null,"abstract":"<p><p>Patient outcomes in advanced renal cell carcinoma (RCC) remain poor, with five-year survival rates ranging from ~10% to 30%. Early projections of therapeutic outcomes could optimize precision medicine and accelerate drug development. While machine learning (ML) models integrating tumor growth inhibition (TGI) metrics have improved survival predictions over traditional models, their application in RCC remains unexplored. Herein, we used TGI metrics and baseline data to evaluate parametric (PM) and semi-parametric (SPM) survival models alongside ML approaches for predicting progression-free (PFS) and overall survival (OS) in 1839 RCC patients from four trials (evaluating sunitinib, axitinib, sorafenib, interferon-alpha, and avelumab + axitinib). Data were split into training (70%) and testing (30%), and feature selection was used to determine parsimonious and robust models. Bootstrap resampling (n = 100) was employed for models' validation, and performance was assessed using C-index and Integrated Brier Score. In brief, training data results demonstrated that tree-based ML models (random survival forest (RSF) and XGBoost) outperformed PM and SPM models in predicting PFS (C-index: 0.783-0.785 vs. 0.725-0.738 for PM and SPM; p < 0.05) and OS (C-index: 0.77-0.867 vs. 0.750-0.758 for PM and SPM; p < 0.05), with RSF achieving better prediction of PFS and OS using only 3-5 covariates, compared to 9-35 with other tested methods. Tree-based methods were also superior in the testing data. SHapley Additive exPlanations revealed nonlinear relationships among top predictors, including TGI metrics, underscoring the ability of tree-based methods to capture complex prognostic interactions. Further validation is required to confirm models' generalizability to additional therapies and patients with differing tumor severity.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":"e70348"},"PeriodicalIF":2.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145349716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network Modeling of Biomarker Systems in Liver Steatosis and Fibrosis.","authors":"Amruta Gajanan Bhat, Murali Ramanathan","doi":"10.1111/cts.70352","DOIUrl":"https://doi.org/10.1111/cts.70352","url":null,"abstract":"<p><p>Metabolic dysfunction-associated fatty liver disease causes hepatic fat accumulation (steatosis) and fibrosis, which can be measured with ultrasound elastography imaging. The dependencies of elastography-derived hepatic steatosis and fibrosis measures with chronic inflammation, disease states, and physiological determinants of drug dosing (PDODD) were assessed. Liver elastography data for n = 5494 participants (50% female, 12-80 years) were obtained from the National Health and Nutrition Examination Survey. Controlled attenuation parameter (CAP) and median liver stiffness (LSM) elastography metrics were used to assess steatosis and fibrosis, and their associations with over 50 key organ systems, disease, and PDODD biomarkers were evaluated with statistical regression, ensemble, and Bayesian learning methods. CAP and LSM increased with age and were greater in males, active liver disease, active hepatitis C, and diabetes or prediabetes. LSM was greater in the presence of congestive heart failure and dialysis. The inflammatory markers C-reactive protein (CRP) and ferritin, body surface area, and hepatic R-value were greater in steatosis and fibrosis. Plasma volume, neutrophil, red blood cell, and platelet counts were greater in steatosis. Drug-induced liver injury index was lower in steatosis and greater in fibrosis. Albumin levels and platelet counts were lower, but the urine albumin-to-creatine ratio was greater in fibrosis. Ensemble learning identified interactions among BMI, age, CRP, ferritin, and liver enzymes contributing to steatosis and fibrosis. Bayesian networks were used to identify directed acyclic graph structures for steatosis and fibrosis. Elastography-derived measures may be useful for individualizing dosing regimens in the presence of metabolic comorbidities presenting dose-selection challenges.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":"e70352"},"PeriodicalIF":2.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145349727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Dose-Escalation Design on the Safety and Development of Anticancer Drugs in Clinical Trials","authors":"Atsushi Nonami,&nbsp;Kensuke Matsuda,&nbsp;Kouta Funakoshi,&nbsp;Ryosuke Kato,&nbsp;Hideaki Takahashi,&nbsp;Yoko Edahiro","doi":"10.1111/cts.70367","DOIUrl":"10.1111/cts.70367","url":null,"abstract":"<p>The operational characteristics of dose-escalation design in phase I studies have been studied using simulations; however, there is limited analysis regarding its effects on the results of clinical trials. We collected the data of 394 clinical trials involving dose-escalation studies for anticancer drugs submitted to the Pharmaceuticals and Medical Devices Agency between 2013 and 2022. We used the internal data of the PMDA and published papers and analyzed outcomes such as enrollment and drug development. We identified model-based designs and rule-based designs as the two primary designs. The median number of dose-limiting toxicity (DLT)-evaluated patients was higher for model-based designs than for rule-based designs. The proportion of rule-based designs was higher in Japanese trials and that of model-based designs was higher in multiregional clinical trials (MRCTs). The determined recommended phase II dose (RP2D) was consistent with the approved dose in all trials (13/13) involving model-based designs and in 84.0% (21/25) of trials involving rule-based designs, although it was not statistically significant. The proportion of progression to the next study phase was 50.0% (61/122) for rule-based designs and 56.3% (36/64) for model-based designs. Similar trends in these outcomes were observed when MRCTs and Japanese trials were examined separately. Model-based designs might require more DLT-evaluated patients; however, they might have different operational capabilities compared with rule-based designs, such as selecting an RP2D consistent with the approved dose. The results might help in selecting the optimal dose-escalation methods in future phase I trials.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202030","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":"Risk and Association of Specific HLA Alleles With Nintedanib-Induced Gastrointestinal Adverse Reactions: A Discovery Study in an Italian Population","authors":"Stefano Mocci,&nbsp;Roberto Littera,&nbsp;Silvia Deidda,&nbsp;Andrea Perra,&nbsp;Matteo Floris,&nbsp;Sabrina Giglio","doi":"10.1111/cts.70371","DOIUrl":"10.1111/cts.70371","url":null,"abstract":"<p>Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. <i>Nintedanib</i> and <i>pirfenidone</i> are the only antifibrotic drugs approved by both the USA and European medicinal agencies, but their efficacy and tolerability remain concerns. This exploratory study investigates the association between genetic variation in the Major Histocompatibility Complex (MHC) region and adverse effects (AEs) of these therapies. HLA genotyping has been previously performed in a discovery cohort of 124 IPF Italian patients, with recorded drug-related AEs. Logistic regression analysis using an additive model identified <i>HLA-C*06:02</i> as a significant risk factor, increasing the likelihood of AEs sixfold in <i>nintedanib</i>-treated patients (<i>p</i> = 0.0043, OR = 6.54, 95% C.I. 1.80–23.75). Notably, gastrointestinal toxicity—the most common AE—was strongly associated with this allele (<i>p</i> = 0.0005, OR = 11.85, 95% C.I. 2.94–47.71). These findings suggest a potential immune-mediated mechanism involving IL-23-driven inflammation and underscore the importance of pharmacogenetic tools in tailoring antifibrotic therapy. Implementing genetic screening could help minimize AEs and improve patient outcomes. Larger studies are warranted to validate these associations and guide personalized treatment strategies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187510","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 Between HNP1-3 and Atherosclerotic Plaque Burden in Subclinical Atherosclerosis and the Mediating Effect of PCSK9","authors":"Ece Yurtseven,&nbsp;Kemal Baysal,&nbsp;Said İncir,&nbsp;Ata Alpay Canbaz,&nbsp;Mert Veznikli,&nbsp;Arzu Baygul,&nbsp;Gamze Aslan,&nbsp;Yasemin Demirci,&nbsp;Erol Gursoy,&nbsp;Kayhan Çetin Atasoy,&nbsp;Dilek Ural","doi":"10.1111/cts.70369","DOIUrl":"10.1111/cts.70369","url":null,"abstract":"<p>Subclinical atherosclerosis is a key predictor of cardiovascular events. While inflammation plays a crucial role in atherosclerosis, the involvement of Human Neutrophil Peptides 1–3 (HNP1-3) in its progression remains unclear. The study investigates the association of HNP1-3 and PCSK9 with coronary atherosclerotic burden and explores the potential mediatory role of PCSK9 in HNP1-3's effect on atherogenesis. Patients who underwent coronary computed tomographic angiography (CCTA) and had subclinical atherosclerosis (luminal stenosis &lt; 50%) or normal coronary arteries were included in this cross-sectional study. HNP1-3 and PCSK9 levels were measured using ELISA, and coronary plaque burden was quantified using the modified Gensini score. Patients with subclinical atherosclerosis had significantly higher levels of HNP1-3 (<i>p</i> &lt; 0.001), PCSK9 (<i>p</i> &lt; 0.001), and lipoprotein(a) [Lp(a)] (<i>p</i> &lt; 0.001) compared to controls. HNP1-3 was an independent predictor of subclinical atherosclerosis (<i>p</i> &lt; 0.001), and its levels positively correlated with the modified Gensini score (<i>p</i> &lt; 0.001). In multinomial logistic regression, higher levels of HNP1-3, PCSK9, and Lp(a) were independently associated with higher modified Gensini score tertiles. Mediation analysis revealed that PCSK9 mediated 48.7% of the effect of HNP1-3 on the modified Gensini score. After adjusting for hsCRP and cardiovascular risk factors, the direct effect of HNP1-3 became statistically insignificant, while the indirect effect via PCSK9 remained significant, suggesting that PCSK9 fully mediates the pro-atherogenic effects of HNP1-3. In conclusion, HNP1-3 is a novel independent predictor of subclinical atherosclerosis and coronary plaque burden, with its effects being mediated through PCSK9. These findings suggest that targeting PCSK9 could mitigate the inflammatory actions of HNP1-3, offering potential therapeutic insights for atherosclerosis prevention.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12480437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193944","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 Pelacarsen, a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Apo(a), in Participants With Mild Hepatic Impairment","authors":"Jing-He Yan,&nbsp;Amanda J. Taylor,&nbsp;Timothy Clough,&nbsp;Elise Burmeister-Getz,&nbsp;Marketa Pazdirkova,&nbsp;Cesare Russo","doi":"10.1111/cts.70344","DOIUrl":"10.1111/cts.70344","url":null,"abstract":"<p>Pelacarsen, an antisense oligonucleotide, directly inhibits plasma lipoprotein(a) production; however, it remains unknown whether hepatic impairment (HI) impacts its safety and pharmacokinetics. This single-dose, open-label, parallel-group, phase I study (NCT05026996) assessed the effect of mild HI on the pharmacokinetics, safety, and tolerability of pelacarsen. Participants (aged 18–75 years) with mild HI (<i>n</i> = 8; Child-Pugh Class A) or healthy controls (<i>n</i> = 9; matched for sex, age, and body weight) received a single subcutaneous injection of 80 mg pelacarsen. Pharmacokinetic parameters were determined using non-compartmental methods. Log-transformed pharmacokinetic parameters were analyzed using a statistical model with group and matching covariates as fixed effects. Least-squares geometric means for each group and geometric mean ratios between participants with mild HI and healthy controls were extracted. The geometric mean ratios for pelacarsen maximum observed concentration (<i>C</i>_max), area under the concentration-time curve from time 0 to time of last quantifiable concentration (AUC_last), and AUC from time 0 to infinity (AUC_inf) were, on average, 7%, 37%, and 50% higher, respectively, in participants with mild HI versus matched controls. The corresponding between-participant variability estimates ranged from 43.0% to 55.2%. The mean elimination half-life (<i>T</i>_1/2) was comparable between the two groups (mild HI, 533 h; healthy matched controls, 518 h). No safety concerns were identified in participants with mild HI or in matched controls. Overall, pelacarsen was well tolerated, and mild HI had no significant effect on <i>C</i>_max. The increase in AUC, likely due to slower early-phase disposition, was within the exposure range tested in the first-in-human study and considered safe.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193949","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":"Effectiveness of Statins for Oxaliplatin-Induced Peripheral Neuropathy: A Multicenter Retrospective Observational Study","authors":"Kenshi Takechi,&nbsp;Takehiro Kawashiri,&nbsp;Keisuke Mine,&nbsp;Soichiro Ushio,&nbsp;Hirofumi Hamano,&nbsp;Noriko Hida,&nbsp;Kenji Momo,&nbsp;Masanobu Uchiyama,&nbsp;Mami Uchida,&nbsp;Mamoru Tanaka,&nbsp;Noriaki Hidaka,&nbsp;Hideki Yasui,&nbsp;Masahiro Ueda,&nbsp;Ryohei Fujii,&nbsp;Misaki Hashimoto,&nbsp;Yasutaka Sakamoto,&nbsp;Kana Uyama,&nbsp;Takahiro Niimura,&nbsp;Yuki Hanai,&nbsp;Ayaka Tsuboya,&nbsp;Keisuke Suzuki,&nbsp;Naoya Kamiyama,&nbsp;Hiromi Hagiwara,&nbsp;Naoto Okada,&nbsp;Yoshito Zamami,&nbsp;Keisuke Ishizawa","doi":"10.1111/cts.70318","DOIUrl":"10.1111/cts.70318","url":null,"abstract":"<p>Chemotherapy-induced peripheral neuropathy, including oxaliplatin-induced peripheral neuropathy (OIPN), can have a negative impact on patient quality of life for months or even years after discontinuation of chemotherapy. Statins are commonly used for lowering cholesterol; however, evidence indicates that statins have multiple pleiotropic effects. Although statins are anticipated to exert neuroprotective actions against OIPN, no large-scale investigations have been conducted in real-world clinical settings. Our investigation aimed to determine if statins protected against OIPN. This multicentre retrospective study enrolled Japanese patients with cancer, including those with colorectal cancer (CRC), who received oxaliplatin-containing chemotherapy between April 2009 and December 2019. Propensity score matching between groups was performed to assess the relationship between the occurrence of OIPN and statin use. Among the examined 2657 patients receiving oxaliplatin, 24.7% had Grade ≥ 2 OIPN. There was no significant difference in the incidence of OIPN between the statin and non-statin groups, even after propensity score matching. However, among the matched patients with CRC (<i>n</i> = 510), statin use was associated with a significantly lower incidence of Grade ≥ 2 OIPN than no statin use (19.8% vs. 28.3%, respectively; <i>p</i> = 0.029). Our findings indicate that statins may protect against OIPN in patients with CRC.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193882","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":"Computational Analysis of Exosome-Derived Signature in TNBC: Integrating Single-Cell and Bulk Transcriptomics for Prognosis Prediction","authors":"Yuan Zhang,&nbsp;Ming Zhao,&nbsp;Lei Hou,&nbsp;Long Jin,&nbsp;Jun Bai,&nbsp;Yunzhi Dang","doi":"10.1111/cts.70368","DOIUrl":"https://doi.org/10.1111/cts.70368","url":null,"abstract":"<p>Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with limited targeted therapeutic options. Exosomes, small membrane vesicles secreted by cells, play a crucial role in intercellular communication and material exchange. However, the role of exosome-related genes (ERGs) in TNBC remains unclear. In here, we analyzed single-cell RNA sequencing (scRNA-seq) from 10 TNBC samples and bulk RNA-seq from TCGA and METABRIC cohorts. Starting with 121 EDPS curated from the breast cancer-specific ExoBCD database, we identified exosome-active cell populations and derived an Exosome-Derived Prognostic Signature (EDPS) through integrative machine learning. Our analysis identified 31,140 cells from TNBC samples, categorized into nine cell types, with epithelial cells exhibiting the highest exosome-related scores. A total of 232 differentially expressed genes (DEGs) related to exosome-related scores were identified, with 19 prognostic genes selected through univariate Cox regression, leading to the construction of an EDPS. Low EDPS scores correlated with poorer clinical outcomes, higher immune infiltrates, and immune-related pathways. Furthermore, we identified notable differences in biological functions and mutation profiles between the two EDPS groups. Additionally, the low EDPS score group exhibited lower tumor immune dysfunction and exclusion (TIDE) scores, immunophenoscore (IPS), and higher immune checkpoint expression, suggesting better immunotherapy outcomes. In conclusion, while derived from exosome-related genes, the EDPS primarily reflects immune-active tumor microenvironments. This signature may help identify TNBC patients likely to benefit from immunotherapy, though further validation of its relationship to exosome biology is needed.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129404","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":"Racing Against the Algorithm: Leveraging Inclusive AI as an Antiracist Tool for Brain Health","authors":"Victor Ekuta","doi":"10.1111/cts.70364","DOIUrl":"https://doi.org/10.1111/cts.70364","url":null,"abstract":"<p>Artificial intelligence (AI) is transforming medicine, including neurology and mental health. Yet without equity-centered design, AI risks reinforcing systemic racism. This article explores how algorithmic bias and phenotypic exclusion disproportionately affect marginalized communities in brain health. Drawing on lived experience and scientific evidence, the essay outlines five design principles—centered on inclusion, transparency, and accountability—to ensure AI promotes equity. By reimagining AI as a tool for justice, we can reshape translational science to serve all populations.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 10","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70364","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129405","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":"Navigating Drug–Drug Interactions in Clinical Drug Development: A Tutorial","authors":"Jesmin Lohy Das,&nbsp;Antoinette (Toni) Ajavon-Hartmann,&nbsp;Virginia (Ginny) D. Schmith","doi":"10.1111/cts.70342","DOIUrl":"10.1111/cts.70342","url":null,"abstract":"<p>This tutorial provides essential guidelines and insights, in addition to regulatory guidance, for the evaluation of drug–drug interactions (DDIs), with a focus on the tools and timing of assessment critical for effective management of inclusion/exclusion criteria during drug development and accurate labeling of investigational drugs. It aims to equip researchers with the knowledge and methodologies required to identify and evaluate DDIs, addressing both victim (investigational drugs that are affected by concomitant medications) and perpetrator (investigational drugs that cause changes in the PK of concomitant medications) interactions. The tutorial explores the mechanistic basis of DDIs, explaining how such interactions can alter drug absorption, distribution, metabolism, and excretion, potentially influencing the benefit-to-risk profile. The tutorial further highlights the tools and methodologies employed in assessing drug–drug interactions (DDIs) across various stages of development. It outlines the importance of in vitro studies for early-stage screening of enzyme- and transporter-mediated interactions to identify potential perpetrators, followed by in vivo studies to confirm these findings. Additionally, it explores the application of computational modeling approaches, such as physiologically based pharmacokinetic (PBPK) modeling and population pharmacokinetic (popPK) approaches, where feasible, to predict both victim and perpetrator interactions prior to or in addition to clinical trials. The aim of this tutorial is to serve as a comprehensive resource for DDI considerations when developing a new molecular entity, supporting researchers during clinical drug development.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70342","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110730","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}