Cts-Clinical and Translational Science最新文献

{"title":"Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants","authors":"Neha Maharao,&nbsp;Donghong Xu,&nbsp;Tyrell J. Simkins,&nbsp;Owen Bowles,&nbsp;Genzhou Liu,&nbsp;Youcef Benattia,&nbsp;Adrienne Griffith,&nbsp;Stephen B. Heitner,&nbsp;Stuart Kupfer,&nbsp;Polina German","doi":"10.1111/cts.70218","DOIUrl":"https://doi.org/10.1111/cts.70218","url":null,"abstract":"<p>Aficamten is a next-in-class, small-molecule, cardiac myosin inhibitor in development for treating hypertrophic cardiomyopathy (HCM). This 2-part study evaluated aficamten's impact on QTc interval in healthy participants. Part A (<i>n</i> = 10) was an open-label study to find the appropriate dose for thorough QT (TQT) evaluation in Part B. Part B (<i>n</i> = 34) was a double-blind, 3-way crossover TQT study conducted as per ICH E14 guidance using negative (placebo) and positive (moxifloxacin) controls. A single 50 mg aficamten dose achieved exposures (C_max range: 124–1660 ng/mL) comparable to the highest clinical dose (20 mg QD) in obstructive HCM patients (NCT05186818; [C_max range: 131–1230 ng/mL]) and was chosen for TQT evaluation. Using concentration-QT (C-QT) modeling, the placebo- and baseline-corrected QT interval using Fridericia's correction (ΔΔQTcF) was −1.82 msec (90% CI: −3.43, −0.214) at peak aficamten concentrations (298.3 ng/mL) following the 50 mg dose. The 90% CI upper bound of ΔΔQTcF for aficamten was &lt; 10 msec at all post-dose time points. Assay sensitivity was established by the 90% CI lower bound for moxifloxacin (ΔΔQTcF) exceeding 5 msec. Aficamten did not cause QTc prolongation (using C-QT and by time point analyses) within observed plasma concentrations up to 1660 ng/mL (aficamten), 213 ng/mL (metabolite CK-3834282), and 343 ng/mL (metabolite CK-3834283). No clinically meaningful effect on electrocardiogram parameters, including absolute QTcF (≤ 450 msec) and change from baseline in QTcF (≤ 30 msec) was noted in aficamten-treated participants. Aficamten was generally well tolerated. In conclusion, there was no evidence of aficamten-mediated QTc prolongation across the therapeutic concentration range in a formal TQT study.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143801696","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":"Identifying Concepts of Physical Activity Which Are Clinically Meaningful to Patients and Care Providers: A Systematic Review of Qualitative Research","authors":"Candice Taguibao,&nbsp;Salma Ajraoui,&nbsp;Jake Centra,&nbsp;Kieran F. Reid,&nbsp;Christina Daskalopoulou,&nbsp;Alberto Conde Freniche,&nbsp;Alan L. Hamilton,&nbsp;Astrid M. H. Horstman,&nbsp;Benjamin X. Collins,&nbsp;Jessilyn Dunn,&nbsp;Elena S. Izmailova","doi":"10.1111/cts.70191","DOIUrl":"https://doi.org/10.1111/cts.70191","url":null,"abstract":"<p>Physical activity (PA) is indispensable for overall health. Sub-optimal PA is linked to reduced quality of life (QOL) and premature death. In clinical research and therapeutics development, defining aspects of PA that are meaningful to patients and care providers is essential for designing tailored interventions, identifying individual contextual factors, and enhancing patient satisfaction and engagement in their own well-being. As digital health technologies (DHTs) measuring PA rapidly evolve, there is an opportunity to further define concepts. A systematic review of qualitative studies to identify concepts of PA that are meaningful to patients and care providers was conducted. Conditions covered included Parkinson's disease, multiple sclerosis, chronic obstructive pulmonary disease, cancer, Duchenne muscular dystrophy, chronic heart failure, sickle cell disease, osteoarthritis, and sarcopenia. We analyzed studies published in the last 20 years utilizing qualitative or mixed methods techniques to describe aspects of PA that patients want to prevent from worsening or improve. Among the 5228 articles returned, 105 studies were included. Thematic synthesis revealed five meaningful aspects of health (MAH) related to PA: ambulation-dependent activities, balance-dependent activities, activities needing upper limb function, changing body positions, and participating in activities of different intensities. Patients also reported PA as important to QOL and influenced by internal and external facilitators and barriers. This research presents new findings related to PA MAHs across various therapeutic areas, which go beyond walking. The findings provide a foundation for defining concepts of interest, measures, and endpoints, with applications in clinical research and care, including patient-focused development of digitally derived measures.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770190","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":"Potential Meets Practicality: AI's Current Impact on the Evidence Generation and Synthesis Pipeline in Health Economics","authors":"Nichola R. Naylor,&nbsp;Noemi Hummel,&nbsp;Carl de Moor,&nbsp;Ananth Kadambi","doi":"10.1111/cts.70206","DOIUrl":"https://doi.org/10.1111/cts.70206","url":null,"abstract":"&lt;p&gt;Health economics and outcomes research (HEOR) plays a key but often underappreciated role in drug development, providing essential evidence to inform healthcare policy and reimbursement by global payors. While there is broad enthusiasm around the potential of artificial intelligence (AI) among HEOR researchers [&lt;span&gt;1&lt;/span&gt;], there are challenges related to its widespread adoption. First, there are a variety of approaches that fall under the AI umbrella, including generative AI based on natural language processing (NLP), large language models (LLMs), and machine learning (ML) methods that classify, cluster, and predict outcomes. Each has potential distinct roles in HEOR, but there are few published evaluations of how these technologies can be practically applied across a breadth of research areas. Second, stakeholder perspectives may impact the value of AI. For example, within the pharmaceutical industry, AI end-users may be interested in more efficient execution of rote tasks, while regulatory bodies and health technology assessment (HTA) agencies, with a wider-ranging public health purview, advise a cautious approach that upholds established scientific practices while ensuring compliance with legal, ethical, data protection requirements and quality standards [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Herein, we examine the current practical and potential future applications of AI across activities critical to payor reimbursement in HEOR. Figure 1 highlights the connectivity of three major HEOR research tools (evidence synthesis, economic modeling and real-world evidence (RWE) generation and evaluation), while also giving an overview of how AI is currently being applied in these fields.&lt;/p&gt;&lt;p&gt;Evidence synthesis refers broadly to activities related to review, curation, and extraction of information from published literature. Within this space, including informal targeted and formal systematic literature reviews (SLRs), AI has been applied to facilitate more efficient and thorough processes via automation, enhanced precision, and the management of large volumes of data while saving time, including:&lt;/p&gt;&lt;p&gt;AI has the potential to transform how researchers analyze RWD and improve their efficiency in generating insights from RWE. AI excels at processing unstructured data, such as text from clinical notes, medical images, and social media posts, using tools like NLP and image recognition [&lt;span&gt;5&lt;/span&gt;]. This has enabled the assessment of the patient journey, treatment patterns, and resource utilization, and can also be used to monitor pharmacovigilance or flu dynamics. ML algorithms, particularly deep learning models, can handle high-dimensional data (e.g., genomics, imaging, and multi-omics data) with millions of variables, and multimodal data (e.g., electronic health record [EHR] data, genomic data, imaging, and sensor data) can be integrated and learned from to find patterns across different types of inputs. As such, these data sources can be used to automatica","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70206","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770377","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":"Identification of Risk Factors and Predictive Indicators for Tigecycline-Associated Hypofibrinogenemia","authors":"Xiaohui Liu,&nbsp;Xuefeng Yuan,&nbsp;Long Wen,&nbsp;Xin Tan,&nbsp;Qian Sui,&nbsp;Jiheng Liu","doi":"10.1111/cts.70213","DOIUrl":"https://doi.org/10.1111/cts.70213","url":null,"abstract":"<p>To investigate the prevalence, clinical manifestations, and risk factors of hypofibrinogenemia after tigecycline use, which can disrupt coagulation and potentially hinder antimicrobial therapy. This observational study was conducted from January to December 2021 at a tertiary general hospital in China. All patients over 18 years old who received tigecycline for more than 48 h were included. After treatment with tigecycline, patients were divided into two groups based on fibrinogen plasma concentrations of less than 2.0 g/L. Multivariable logistic regression was performed to identify risk factors for hypofibrinogenemia associated with tigecycline. A total of 50 patients (mean age 71.3 ± 20.2 years) were analyzed. The median duration of treatment was 8 days (range: 3 to 20 days). Among the 24 patients who developed hypofibrinogenemia, three gastrointestinal bleeding events were observed, and four of these patients required fibrinogen administration. We identified the total therapeutic dose (odds ratio (OR) = 15.28, 95% confidence interval (CI) 2.10–111.02, <i>p</i> = 0.01) and a baseline direct bilirubin level greater than 0.4 mg/dL (OR = 5.79, 95% CI 1.13–27.98, <i>p</i> = 0.04) as risk factors for tigecycline-induced hypofibrinogenemia. Conversely, a baseline fibrinogen level (OR = 0.53, 95% CI 0.29–0.97, <i>p</i> = 0.04) appeared to be a protective factor. Healthcare professionals should be aware that the administration of tigecycline may be associated with hypofibrinogenemia and severe adverse reactions. Regular monitoring of coagulation is essential, particularly for patients with liver dysfunction, low baseline fibrinogen levels, elevated baseline direct bilirubin levels, or those receiving higher total therapeutic doses.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769974","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":"New Function for Safety Signal Monitoring in MID-NET®: The Case of an Anti-COVID-19 Drug","authors":"Yusuke Okada,&nbsp;Takashi Ando,&nbsp;Fumitaka Takahashi,&nbsp;Kenichi Watanabe,&nbsp;Kazuhiro Kajiyama,&nbsp;Tomoaki Hasegawa,&nbsp;Satomi Inomata,&nbsp;Yuki Kinoshita,&nbsp;Shinya Watanabe,&nbsp;Yoshiaki Uyama","doi":"10.1111/cts.70208","DOIUrl":"https://doi.org/10.1111/cts.70208","url":null,"abstract":"<p>Real-world data play a key role in monitoring drug safety at the post-marketing stage. However, challenges on how to rapidly and continuously obtain analytical results of many outcomes for drug safety signal monitoring still remain. We aimed to establish a rapid and continuous monitoring tool for drug safety assessment based on real-world data in Japan. An automated process for a new-user cohort design with customizable analytical conditions was developed. The customizable analytical conditions include exposure and control drugs, 46 outcomes related to liver and kidney functions, blood tests, biomarkers, and time period of interest. Statistical analyses were performed to evaluate the outcome status (present/absent) and calculate the adjusted hazard ratio, with a 95% confidence interval of exposure to control. We monitored the safety signals of an anti-COVID-19 drug (combination of tixagevimab and cilgavimab) and compared them with those of two controls (peramivir and the combination of casirivimab and imdevimab) to examine the practical utility of this new tool. Our study provided helpful information (e.g., new safety signals) on many outcomes at multiple time points, which could enhance the understanding of drug safety profiles soon after approval. Our function can be used to rapidly and continuously monitor drug safety signals and contribute to strengthening drug safety monitoring in Japan.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749318","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 “Toward an Effective Translational Science Engine”","authors":"","doi":"10.1111/cts.70219","DOIUrl":"https://doi.org/10.1111/cts.70219","url":null,"abstract":"<p>Ioachimescu OC, Shaker R. Toward an Effective Translational Science Engine. <i>Clin Transl Sci</i>. 2024 Nov;17(11):e70069. doi: 10.1111/cts.70069. PMID: 39539022; PMCID: PMC11561134.</p><p>The funding statement should read “NIH (NCATS) UL1 TR001436 (MCW IRB# FP00015891)” rather than “CTSA: FP00015891.”</p><p>The corresponding author's email address should be changed to <span>[email protected]</span>.</p><p>Affiliation 1 should be Milwaukee, Wisconsin, not Hartland, Wisconsin.</p><p>The address for the corresponding author should be 8701 Watertown Plank Rd., Suite M1350, Milwaukee, WI 53226, USA.</p><p>We apologize for this error.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761961","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 Edges of Clinical Pharmacology: A Narrative Review on Religious and Sociocultural Influences in Drug Management","authors":"Salvatore Di Maria,&nbsp;Alessio Provenzani","doi":"10.1111/cts.70217","DOIUrl":"https://doi.org/10.1111/cts.70217","url":null,"abstract":"<p>Scientific advancements in pharmacology have revolutionized disease management, significantly enhancing global health. Innovations like biological therapies and mRNA vaccines underscore the field's capacity to address complex conditions and global crises. However, significant challenges remain, including individual biological variations and ethical, cultural, and religious barriers, which complicate treatment access and equity. This review explores these global barriers, emphasizing the intersection of pharmacology with diverse cultural contexts. Religious beliefs often shape attitudes toward treatments. For example, fasting during Ramadan requires careful adjustments to diabetes management protocols, while Jehovah's Witnesses' refusal of blood transfusions necessitates alternative solutions like hemoglobin-based oxygen carriers and cell-saving devices. In Africa, cultural resistance to blood sampling impacts disease diagnosis and therapeutic drug monitoring, highlighting the need for culturally sensitive healthcare strategies. Dietary restrictions rooted in religious practices, such as Kashrut and Halal, further complicate drug formulation. Medications containing animal-derived ingredients may be rejected, necessitating plant-based or certified alternatives. Emergency exceptions in Islamic and Jewish law provide some flexibility, but overall, these challenges underscore the necessity of innovative solutions to ensure inclusive healthcare. This narrative review advocates for an equitable approach to pharmacological research and clinical practice, emphasizing the importance of dialogue and cultural awareness. By addressing ethical dilemmas and respecting diverse traditions, pharmacology can better serve global populations, bridging gaps between modern medicine and cultural values. The review calls for tailored strategies that uphold both medical efficacy and cultural sensitivity to advance healthcare equity worldwide.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741187","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":"Effect of Cladribine Tablets on the Pharmacokinetics of a Combined Oral Contraceptive in Pre-Menopausal Women With Relapsing Multiple Sclerosis","authors":"Robert Hermann,&nbsp;Kerstin Hellwig,&nbsp;Sumedh Gaikwad,&nbsp;Andrew Galazka,&nbsp;Afrim Bytyqi,&nbsp;Dominic Jack,&nbsp;Axel Krebs-Brown,&nbsp;Claudia Vetter,&nbsp;Axel Nolting,&nbsp;Karthik Venkatakrishnan,&nbsp;Jennifer Q. Dong","doi":"10.1111/cts.70204","DOIUrl":"https://doi.org/10.1111/cts.70204","url":null,"abstract":"<p>This study assessed the effect of cladribine tablets (CladT) on the pharmacokinetics (PK) of a combined oral contraceptive (COC) in pre-menopausal women with relapsing multiple sclerosis. It was a randomized, double-blind, two-period, two-sequence crossover study to assess steady-state plasma PK (area under the concentration–time curve and peak concentration) of COC (ethinylestradiol [EE] 30 μg and levonorgestrel [LNG] 150 μg) when co-administered with CladT or placebo. Participants received 2 weeks of active CladT treatment per course (Weeks 1 and 5 per year) to have a cumulative dose of 3.5 mg/kg over 2 years as per label. Of the 24 randomized participants, 23 completed the study. The results showed that the concentration–time profiles as well as PK parameters of EE and LNG in the plasma were similar when co-administered with CladT or placebo. Analysis of variance confirmed the bioequivalence of EE and LNG in COC when co-administered with either CladT or placebo. All participants were adequately exposed to cladribine. Repeat-dose administration of CladT had no apparent effect on serum luteinizing hormone, follicle-stimulating hormone, progesterone, or sex hormone-binding globulin concentrations during concomitant treatment with COC. Co-administration with COC did not change the known safety and tolerability profile of CladT and did not alter the PK of EE or LNG in a COC during the study. Therefore, the concomitant use of CladT is not expected to decrease the efficacy of COCs containing EE and LNG.</p><p><b>Trial Registration:</b> EudraCT Number: 2018-001015-70.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70204","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749418","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 First-In-Human Phase 1 Study to Evaluate the Safety and Tolerability of LEM-S401, a Novel siRNA-DegradaBALL Drug Targeting CTGF in Healthy Adults","authors":"Ha-Yeon Kim,&nbsp;Jaeso Cho,&nbsp;Min Kyu Park,&nbsp;Dal-Hee Min,&nbsp;Jun Gi Hwang,&nbsp;Cheolhee Won","doi":"10.1111/cts.70207","DOIUrl":"https://doi.org/10.1111/cts.70207","url":null,"abstract":"<p>This study evaluated the safety, tolerability, and pharmacokinetics of LEM-S401, a novel siRNA therapeutic with DegradaBALL, a mesoporous silica nanoparticle-based delivery system. LEM-S401 is designed to deliver siRNA targeting connective tissue growth factor (CTGF) to fibroblasts for treating hypertrophic scars and keloids, both of which result from abnormal collagen proliferation. LEM-S401, containing unmodified siRNA LEM-17234 encapsulated in DegradaBALL nanoparticles, was administered subcutaneously to healthy adults in a randomized, double-blind, placebo-controlled, single-ascending dose study. Safety and tolerability assessments included vital signs, adverse events (AEs), laboratory tests, and cytokine levels. Pharmacokinetic analysis of LEM-17234 and silicon (Si), the primary component of DegradaBALL, was performed using blood samples collected at specified time points. LEM-S401 demonstrated a favorable safety and tolerability profile with only mild, self-resolving injection site reactions including pain and erythema. No systemic AEs were observed, and cytokine levels showed no significant changes between the treatment and placebo groups. Pharmacokinetic analysis revealed that LEM-17234 was below the plasma detection limit, indicating no notable systemic exposure of siRNA, while Si showed no dose-dependent systemic exposure, suggesting minimal systemic circulation of the mesoporous silica nanoparticles. These findings suggest DegradaBALL effectively encapsulates and delivers siRNA locally without significant systemic exposure. The novel DegradaBALL delivery system enables the stable and targeted delivery of siRNA, which presumably overcomes challenges related to siRNA instability and off-target effects. LEM-S401 has the potential to advance the treatment of fibrotic skin diseases such as keloids and hypertrophic scars by delivering siRNA directly to fibroblasts, thereby inhibiting excessive collagen production.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT04707131. https://clinicaltrials.gov/study/NCT04707131?cond=NCT04707131&amp;rank=1</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70207","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741636","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":"CYP3A Genotype Is Associated With Variability in the Exposure and Clearance of the Novel Oncogenic Transcription Inhibitor Lurbinectedin","authors":"Rubin Lubomirov,&nbsp;Laura Pérez-Ramos,&nbsp;Salvador Fudio,&nbsp;Eduardo Asín-Prieto,&nbsp;Laura Ibarra-Gómez,&nbsp;Pablo Zubiaur","doi":"10.1111/cts.70173","DOIUrl":"https://doi.org/10.1111/cts.70173","url":null,"abstract":"<p>Lurbinectedin is an oncogenic transcription inhibitor indicated for the treatment of small cell lung cancer (SCLC), which has also shown activity against other malignancies. In this work, two independent cohorts of 180 (discovery cohort) and 719 (validation cohort) cancer patients receiving lurbinectedin in Phases I, II, or III clinical trials were enrolled. Using a population pharmacokinetic (popPK) model of the discovery cohort, patients with extremely high (<i>n</i> = 10, cohort 1) and low (<i>n</i> = 10, cohort 2) etaCL values (i.e., a variable used as a surrogate of unexplained CL interindividual variability) were identified. They were sequenced for 42 candidate genes involved in lurbinectedin pharmacokinetics. A total of 34 variants located in 20 genes were significantly associated with lurbinectedin etaCL; the best nine hits (located in <i>CYP3A5, CYP3A4, ABCB1, ARNT, NR5A2, NR1H4</i>, and <i>FOXA3</i>) were subsequently genotyped in the validation cohort. A strong additive association between <i>CYP3A4</i> and <i>CYP3A5</i> genotypes (informed as a CYP3A activity score [AS] variable) and lurbinectedin clearance (CL) and exposure was confirmed, for example, patients with an AS of 3, 2, or 1 showed a 2.3-, 1.6-, and 1.5-fold higher total lurbinectedin CL compared to those with an AS of 0 and 2.3-, 1.8-, and 1.6-fold higher unbound lurbinectedin CL. In conclusion, preemptive <i>CYP3A</i> genotyping may offer a valuable approach for personalizing treatment with lurbinectedin in cancer patients.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717395","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}