Cts-Clinical and Translational Science最新文献

{"title":"Bench to Bedside Modeling of mRNA Encoding IgG Using a Multiscale Mechanistic Pharmacokinetic-Toxicokinetic (PK-TK) Model: A Case Study With Anti-Claudin 18.2","authors":"Devam A. Desai,&nbsp;Rodrigo Cristofoletti","doi":"10.1111/cts.70356","DOIUrl":"10.1111/cts.70356","url":null,"abstract":"<p>In vivo expression of mRNA-encoded antibodies offers a novel platform for targeted therapies. However, translating preclinical findings to clinical applications remains challenging due to complex processes, including nanoparticle delivery, cellular uptake, mRNA translation, and target binding. This study developed a multiscale mechanistic pharmacokinetic-toxicokinetic (PK-TK) model to characterize and predict the in vivo behavior of an mRNA therapeutic encoding an anti-claudin 18.2 IgG, scaling from preclinical models to human predictions. The model integrates key processes: (i) lipid nanoparticle (LNP)-mediated delivery and endocytosis via low-density lipoprotein receptors (LDLR), (ii) endosomal escape and mRNA release, (iii) cytoplasmic mRNA translation into IgG, (iv) IgG systemic distribution and target binding, and (v) transient cytokine elevation triggered by exogenous mRNA. Model development leveraged published in vitro and in vivo data from mice, rats, and non-human primates (NHPs). Allometric scaling principles and inter-species differences in LDLR expression enabled human translation. Sensitivity analysis identified critical translational bottlenecks. The model successfully recapitulated the time course of mRNA, expressed IgG, and cytokine/chemokine levels in mice following intravenous administration. For human predictions, simulations of receptor occupancy and systemic exposure of encoded antibody informed the selection of 0.01 mg/kg as the starting dose for first-in-human trials. By highlighting species-specific differences in nanoparticle processing and mRNA translation kinetics, this framework provides a rational basis for dose selection. Applicable to other mRNA-based protein therapeutics, this multiscale PK-TK model enhances translational predictability, streamlining clinical 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.70356","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110806","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":"Role of Trimethylamine N-Oxide in Assessing Plaque Instability of the Culprit Lesion in Chinese Patients With ST-Elevation Myocardial Infarction: Insights From a 7-Year Long-Term Follow-Up Study","authors":"Lili Xiu,&nbsp;Peng Zhao,&nbsp;Xia Gu,&nbsp;Bo Yu","doi":"10.1111/cts.70357","DOIUrl":"10.1111/cts.70357","url":null,"abstract":"<p>This study investigated the relationship between trimethylamine N-oxide (TMAO) levels and plaque instability in Chinese patients with ST-elevation myocardial infarction (STEMI) using optical coherence tomography (OCT), with a 7 -year follow-up. Between January 1, 2017, and December 31, 2018, 188 Chinese patients with STEMI who underwent OCT at the Second Affiliated Hospital of Harbin Medical University were enrolled. Patients were stratified into low TMAO (≤ 2.54 μM) and high TMAO (&gt; 2.54 μM) groups. The primary endpoint was major adverse cardiovascular events (MACE: all-cause mortality, reinfarction, target vessel revascularization, and stroke). Compared with the low TMAO group, the high TMAO group showed a higher incidence of plaque rupture and a lower incidence of plaque erosion. Laboratory findings revealed significantly elevated NT-proBNP levels in the high TMAO group. OCT analyzes demonstrated greater plaque length and more frequent microchannels in the high TMAO group. During follow-up, both TMAO and NT-proBNP were independently associated with 7-year MACE. Receiver operating characteristic analysis identified TMAO as a predictor of MACE, with a sensitivity of 59.5% and a specificity of 65.8%. In conclusion, elevated TMAO levels were associated with adverse plaque characteristics and independently predicted long-term cardiovascular events in Chinese STEMI patients. These findings suggest that TMAO may serve as a valuable biomarker for assessing plaque instability and improving risk stratification in this population.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092887","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":"Ibrexafungerp: Mechanism of Action, Clinical, and Translational Science","authors":"Adelynne H. Walley,&nbsp;Lauren N. Dupuis,&nbsp;Erica L. Woodahl,&nbsp;Shayna R. Killam","doi":"10.1111/cts.70362","DOIUrl":"10.1111/cts.70362","url":null,"abstract":"<p>Ibrexafungerp is a first-in-class triterpenoid antifungal that targets β-(1,3)-glucan synthase in fungal cell wall development. It is indicated for vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis (RVVC) in adult and post-menarchal pediatric females. The drug was approved in 2021 and 2022 for VVC and RVVC, respectively. Research is ongoing to evaluate the safety of ibrexafungerp in pregnancy and lactation as well as to explore intravenous and oral formulations for invasive candidiasis and invasive aspergillosis. Ibrexafungerp binds and inhibits β-(1,3)-glucan synthase that is essential for the synthesis of β-(1,3)-D-glucan, a key polymer in the fungal cell wall, leading to cell lysis and death. This mechanism of action varies from that of the current VVC therapy, fluconazole, which makes ibrexafungerp a primary candidate for treating fluconazole-resistant patient cases. The drug is distributed into vaginal tissue at higher concentrations and has increased efficacy at lower pH compared to fluconazole, indicating a therapeutic advantage for VVC. Ibrexafungerp was generally well-tolerated in most participants throughout clinical trials. The most commonly reported treatment-emergent adverse events were headache, dizziness, and gastrointestinal-related effects. The efficacy of ibrexafungerp was found to be comparable to fluconazole and superior to placebo as seen in key clinical trials: DOVE (NCT03253094) and VANISH303 (NCT03734991). We reviewed the regulatory approval process of ibrexafungerp, including key clinical trials and in-depth analyses of pivotal studies related to the drug's clinical efficacy and safety. Additionally, we reviewed the drug's unique mechanism of action and the pharmacokinetic and pharmacodynamic characteristics essential for its use in VVC and RVVC.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70362","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088027","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":"Utilization of Machine Learning Approaches for Drug Clearance Prediction and Population Pharmacokinetic Covariate Analysis","authors":"Atul Rawal,&nbsp;Jiayi Ou,&nbsp;Hao Zhu,&nbsp;Zuben Sauna,&nbsp;Million A. Tegenge","doi":"10.1111/cts.70359","DOIUrl":"10.1111/cts.70359","url":null,"abstract":"<p>Population pharmacokinetic (popPK) analysis is routinely used to evaluate drug clearance and covariate effects on pharmacokinetic parameters to support dosing recommendations. While stepwise methods are traditionally employed for covariate identification, artificial intelligence (AI) and machine learning (ML) approaches offer promising alternatives for enhancing these analyses. This proof-of-concept study illustrates the application of AI/ML and explainable artificial intelligence (XAI) techniques for drug clearance prediction and covariate analysis using two distinct datasets for the drugs methotrexate and remifentanil. For the larger methotrexate dataset, we utilized multiple ML models including convolutional neural networks, logistic regression, and gradient boosting and highlighted exceptional performance (<i>R</i>² for accuracy &gt; 0.96) in clearance prediction. XAI via SHapley Additive exPlanations (SHAP) analysis is utilized to identify vital covariates impacting clearance. Here, XAI techniques are utilized to explore how different AI/ML approaches might impact the interpretation of relationships among covariates. By examining these methods, we seek to better understand their respective strengths, limitations, and potential to provide insights for popPK analysis. The second example used a smaller dataset for the drug remifentanil and included pediatric to adult populations. Here, the performance of the ML models was more modest (maximum <i>R</i>² of 0.75), highlighting the dependence of ML techniques on adequate sample sizes. SHAP analysis confirmed age and weight as critical covariates for the clearance of remifentanil. Our findings demonstrate that AI/ML approaches can provide accurate clearance predictions and identify potentially overlooked covariates in an unbiased, hypothesis-free manner. However, this study also emphasizes important limitations, including the requirement for sufficiently large datasets and the drug-specific nature of trained models. These proof-of-concept examples illustrate how AI/ML methods can complement traditional pharmacokinetic analyses, offering additional insights while maintaining scientific rigor.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70359","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088043","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":"A Multi-Scale Mechanistic Model of Ulcerative Colitis to Investigate the Effects of Selective Suppression of IL-6 Trans-Signaling","authors":"Ola Sternebring,&nbsp;Nikhil Patidar,&nbsp;Arjun Ravi,&nbsp;Ruth Carcillo,&nbsp;Aymeric Rivollier,&nbsp;Zhongyu Wang,&nbsp;Sai Phanindra Venkatapurapu,&nbsp;Marcelo Behar,&nbsp;Simon Read,&nbsp;Rose Szabady,&nbsp;Jørgen Sørensen,&nbsp;Paul M. D'Alessandro,&nbsp;Philippe Pinton","doi":"10.1111/cts.70366","DOIUrl":"10.1111/cts.70366","url":null,"abstract":"<p>Interleukin 6 (IL-6) has previously been identified as playing a role in ulcerative colitis (UC) by activating the signal-transducing element gp130 through ligation of either the membrane-bound or soluble IL-6 receptor (termed classic and trans-signaling respectively). It has been proposed that selective inhibition of trans-IL-6 signaling could ameliorate the deleterious, pro-inflammatory effects of IL-6, while preserving the homeostatic activity of classic IL-6 signaling. We developed an <i>in silico</i>, mechanistic model of UC in two stages to compare the biological effects that result from inhibition of classic and trans-IL-6 signaling. In the first stage, we developed a limited-scope model of IL-6 signaling to establish the quantitative properties of classic and trans-signaling pathways on a short timescale following stimulation with IL-6. The model included both a pan-inhibitor of IL-6 classic and trans-signaling and a soluble gp130-Fc that selectively inhibited trans-signaling. In the second stage, we developed a multi-scale model of UC to study the pharmacodynamic effects of cytokine signaling inhibition and optimize treatment regimens. Across three virtual experiments, both selective and global suppression of IL-6 signaling were associated with a transition away from an inflammatory state in patients with moderate to severe inflammatory activity. In our multi-scale model, we identified a dose–response relationship between selective inhibition of trans-IL-6 signaling and tissue regeneration. Moreover, selective inhibition of trans-IL-6 signaling effectively suppressed inflammation and induced faster gut tissue healing than global IL-6 suppression. These findings suggest that global suppression of IL-6 signaling could negatively affect IL-6-induced regeneration activity, whereas this effect is less likely for selective inhibition.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70366","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087998","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, Pharmacodynamics, and Immunogenicity of CM313 in Healthy Participants: An Open-Label/Double-Blind, Randomized, Placebo-Controlled Phase 1 Trial","authors":"Shuyan Yu,&nbsp;Junzhen Wu,&nbsp;Junxue Zhao,&nbsp;Jinjie He,&nbsp;Hongyue Yan,&nbsp;Xiang Zhang,&nbsp;Yifan Yang,&nbsp;Han Song,&nbsp;Qiaoyun Hou,&nbsp;Bujing Guo,&nbsp;Yanping Qiu,&nbsp;Bo Chen,&nbsp;Yu Xue,&nbsp;Jing Zhang","doi":"10.1111/cts.70334","DOIUrl":"10.1111/cts.70334","url":null,"abstract":"<p>CM313, a novel humanized anti-CD38 monoclonal antibody, has demonstrated therapeutic potential in autoimmune diseases. This Phase 1 trial evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy participants following single ascending doses of CM313. Fifty-one participants received CM313 or placebo by SC injection at doses of 150 mg (1:1), 300 mg (2:1), and 600 mg (2:1), or by IV infusion at 8 mg/kg (2:1). All completed the trial. Treatment-emergent adverse events occurred in 90.9% of CM313-treated participants and 83.3% of placebo-treated participants, all mild or moderate. No serious adverse events were reported. SC injections of CM313 demonstrated a notably lower incidence of infusion-related reactions (600 mg SC: 20%) than IV infusion (8 mg/kg IV: 60%). CM313 exhibited nonlinear pharmacokinetics. Following a single SC dose, the median <i>T</i>_max was 2.00–3.00 days, mean <i>C</i>_max was 4.75–87.40 μg/mL, mean AUC_0-<i>t</i> was 20.29–1262.50 day*μg/mL, mean <i>V</i>_z/<i>F</i> was 2.63–21.20 L, mean clearance was 0.50–7.90 L/day, and mean half-life was 1.85–3.90 days. The bioavailability of the 600 mg SC dose was 66% of the 8 mg/kg IV dose. CM313 induced rapid and sustained reductions in total IgA, IgE, IgG, and IgM levels by 40%–80% from baseline. Both SC and IV formulations demonstrated potent CD38 binding activity and markedly depleted NK cells by ≥ 90% within 2 days. CM313 also achieved 80%–90% CD38 receptor occupancy on B cells, T cells, and monocytes within 1 week. Overall, single doses of CM313 demonstrated favorable safety, tolerability, PK, and PD in healthy participants.</p><p><b>Trial Registration:</b> ClinicalTrials.gov (NCT06285227)</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088065","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":"Correlation Between Chimeric Antigen Receptor T-Cell Pharmacokinetic Data Measured by Flow Cytometry and Quantitative Polymerase Chain Reaction","authors":"Wenjie Wang,&nbsp;Xiaojia Liu,&nbsp;Tairan Yang,&nbsp;Jing Wang,&nbsp;Jin Liu,&nbsp;Yuqing Wang,&nbsp;Jie Yu,&nbsp;Tracy Luo,&nbsp;Xiaodi Wang,&nbsp;Jian Li,&nbsp;Chuan Wang,&nbsp;Ning Chen,&nbsp;Dong Geng,&nbsp;Da Xu","doi":"10.1111/cts.70354","DOIUrl":"10.1111/cts.70354","url":null,"abstract":"<p>Chimeric antigen receptor (CAR)-T cells have antitumor efficacy in hematological and solid malignancies. Unlike small molecules or antibodies, CAR-T cells have unique kinetic profiles (distribution, expansion, contraction, and persistence). To quantify these dynamics, flow cytometry and qPCR are commonly used, each with distinct advantages and limitations. We analyzed the correlation between flow cytometry and qPCR quantification of CAR-T cells in subjects from 4 phase 1 clinical studies (individually and combined). We also explored factors that affect calculations of CAR-T cells and CAR transgene copy number, how these affect pharmacokinetic (PK) parameters determination for clinical studies, and associations with pharmacodynamic factors such as cytokine levels. We demonstrate that CAR transgene copy number is more highly correlated with the ratio of CAR-T cells to white blood cells (WBCs) than with the actual number of CAR-T cells, indicating that CAR transgene copy number is related to the percentage of CAR-T cells in blood. The low level of correlation between CAR transgene copy number and CAR-T cells may be due to differences in the ratio of CAR-T cells to WBCs at some time points. Meanwhile, flow cytometry and qPCR PK values correlated with cytokine levels; flow cytometry data had a higher correlation coefficient (<i>r</i>) and lower <i>p</i>-values than qPCR data. These findings increase our understanding of potential causes of inconsistencies in PK and pharmacodynamic parameters analyzed during studies of CAR-T cell therapy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088067","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":"Bridging Pharmacokinetics and Pharmacodynamics: A PBPK/PD Model-Based Approach for Deferasirox Dosing in Transfusion-Dependent Thalassemia","authors":"Watchara Sakares,&nbsp;Udomsak Udomnilobol,&nbsp;Xian Pan,&nbsp;Kittika Yampayon,&nbsp;Supachai Ekwattanakit,&nbsp;Vip Viprakasit,&nbsp;Chanin Limwongse,&nbsp;Somdet Srichairatanakool,&nbsp;Polsak Teerawonganan,&nbsp;Sumate Kunsa-ngiem,&nbsp;Vipada Khaowroongrueng,&nbsp;Isariya Techatanawat,&nbsp;Thomayant Prueksaritanont,&nbsp;Varalee Yodsurang","doi":"10.1111/cts.70355","DOIUrl":"10.1111/cts.70355","url":null,"abstract":"<p>Patients with transfusion-dependent thalassemia (TDT) require lifelong blood transfusions, resulting in excessive iron accumulation and necessitating effective chelation therapy. Deferasirox (DFX) is the primary oral iron chelator for managing iron overload; however, the response to this treatment varies substantially within different individuals, potentially because of differences in its pharmacokinetics (PK) and pharmacodynamics (PD). This study aimed to develop a physiologically based pharmacokinetic–pharmacodynamic (PBPK/PD) DFX model, integrating hepatic- and transfusion-derived iron burdens to assess their impact on DFX PK and optimize dosing. The model was developed using clinical PK data from Caucasian and Thai populations, comprising healthy individuals and patients with TDT. TDT-specific physiological parameters were incorporated into the TDT model. The verified model was applied to predict the targeted DFX dose required to achieve a 25% reduction in the liver iron concentration (LIC) from baseline after 6 months of treatment based on the baseline LIC and blood transfusion regimen. The model demonstrated high predictive accuracy across populations, identifying the effects of iron levels on DFX clearance. Simulations revealed that patients with higher baseline LIC were more likely to achieve the targeted reduction, whereas those with lower LIC required higher doses because of slower iron mobilization. A reduced blood transfusion regimen was associated with improved therapeutic outcomes at the same DFX dose. The PBPK/PD model proposed targeted DFX doses to achieve a 25% reduction based on baseline LIC levels and transfusion regimen, emphasizing the requirement for individualized dosing strategies based on iron burden and blood transfusion patterns to maximize clinical outcomes.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082343","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":"Correction to “Implementing Pain, Agitation, Delirium, and Sleep Deprivation Protocol in Critically Ill Patients: A Pilot Study on Pharmacological Interventions”","authors":"","doi":"10.1111/cts.70363","DOIUrl":"10.1111/cts.70363","url":null,"abstract":"<p>Luetrakool P, Taesotikul S, Susantitapong K, Suthisisang C, Morakul S, Sutherasan Y, Tangsujaritvijit V, Dilokpattanamongkol P. Implementing pain, agitation, delirium, and sleep deprivation protocol in critically ill patients: A pilot study on pharmacological interventions. <i>Clin Transl Sci</i>. 2024 Mar;17(3):e13739. doi: 10.1111/cts.13739. PMID: 38421247; PMCID: PMC10903435.</p><p>In Paragraph 3 of the “Study design” section, the following sentence was published with an incorrect approval number:</p><p>“This study was approved by the ethical clearance committee on human rights related to research involving human subjects, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, with approval number MURA2020/150.”</p><p>This should have read:</p><p>“This study was approved by the ethical clearance committee on human rights related to research involving human subjects, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, with approval number MURA2020/151.”</p><p>We apologize for this error.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12441202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076534","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":"A Modeling Investigation of the CYP1A Drug Interactions of Riluzole","authors":"Paul Malik,&nbsp;Paola Mian,&nbsp;Jinsy Andrews,&nbsp;Matthew Rosebraugh,&nbsp;Senda Ajroud-Driss","doi":"10.1111/cts.70358","DOIUrl":"10.1111/cts.70358","url":null,"abstract":"<p>Cytochrome-P-450 (CYP)1A2 has been considered the major enzyme metabolizing riluzole since its approval. However, the inhibitor that was used in the original experiments, α-naphthoflavone, is also a potent inhibitor of CYP1A1. In this work, physiologically based pharmacokinetic (PBPK) modeling investigates the interplay between CYP1A1 and CYP1A2 and the relevance to drug–drug interactions. Following review of clinical and non-clinical data from literature, the relative contributions of CYP1A1, CYP1A2, and UGT1A8/9 to riluzole metabolism were assigned as 60%, 30%, and 10%, respectively. The model was calibrated on single-dose pharmacokinetic (PK) data from healthy subjects. The translational potential of the model was verified by predicting riluzole PK in people with amyotrophic lateral sclerosis, spinal muscular atrophy, advanced age, renal impairment, and hepatic impairment, and when administered with a high-fat meal. The relative contributions of CYP1A1 and CYP1A2 to metabolism were verified through prediction of an observed drug–drug interaction between riluzole and fluvoxamine—a strong CYP1A2 inhibitor and a weak CYP1A1 inhibitor—in children with obsessive–compulsive disorder. Overall, evidence suggests that CYP1A1 is a major enzyme metabolizing riluzole, and that CYP1A2 has similar or lower importance. Only clinically relevant inhibitors of both enzymes may pose a safety concern when administered with riluzole. Strong CYP1A1 inhibitors and strong CYP1A2 inhibitors may be used with caution if they do not significantly modulate the other enzyme. Concomitant use of CYP1A1 inducers may be reconsidered where possible. The enzymatic contributions to riluzole metabolism should be reconsidered after formal drug–drug interaction studies are completed.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 9","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12441310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076562","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}