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Inadequate representation of individuals of African ancestry in pharmacogenetics of tamoxifen research Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-19 Keneuoe Cecilia Nthontho, Andrew Khulekani Ndlovu, Giacomo Maria Paganotti
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Bioavailability of a novel sustained‐release pellet formulation of 5‐flucytosine in healthy‐fed participants for use in patients with cryptococcal meningitis Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-18 Nabila Ibnou Zekri Lassout, Vishal Goyal, Edrich Krantz, Francois Simon, Anouk Neven, Johanna Eriksson, Amaria Saayman, Vijay Satam, Carol Ruffell, Sarika Victor, Marylore Chenel, Aljosa Celebic, Henri Caplain, Jean‐Yves Gillon, Abhijit Deshmukh, Amit Antarkar, Eric Sjögren, Isabela Ribeiro
Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub‐Saharan Africa. 5‐flucytosine (5‐FC) is a unique, brain‐permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5‐FC has a short plasma half‐life, requiring 6‐hourly
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Drug–drug interactions of icenticaftor (QBW251) with a 5‐probe cytochrome P450 cocktail and oral contraceptives Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-17 Felix Huth, Ulrike Glaenzel, Anton Drollmann, Wendy Weis, Julia Zack, Lidiya Bebrevska
A drug–drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor (QBW251) on the pharmacokinetics (PK) of a 5‐probe cytochrome P450 (CYP) substrate cocktail, guided by in vitro studies in human hepatocytes and liver microsomes. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl
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Paired comparisons of venetoclax concentration in cerebrospinal fluid, bone marrow, and plasma in acute leukemia patients Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-17 Yuan Jian, Feifei Han, Ying Zhu, Chuanying Geng, Yanru Zhang, Yin Wu, Yun Leng, Wenming Chen, Zhuoling An, Hong‐Hu Zhu
Venetoclax, a small molecule inhibitor of BCL‐2, has demonstrated efficacy in treating acute leukemias and has been recommended as one of the first‐line anti‐leukemia therapies. Although venetoclax has been suggested to probably possess the ability to penetrate the central nervous system (CNS), current data to elucidate the characteristics of venetoclax in cerebrospinal fluid (CSF), bone marrow (BM)
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Prevalence of actionable pharmacogenetic variants and high‐risk drug prescriptions: A Swiss hospital‐based cohort study Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-12 Flavia Hodel, Maria B. De Min, Christian Wandall Thorball, Claire Redin, Peter Vollenweider, François Girardin, Jacques Fellay
Drug type and dosing recommendation have been designed and optimized based on average response in the general population. Yet, there is significant inter‐individual variability in drug response, which results in treatment inefficacy or adverse drug reactions in a subset of patients. This is partly due to genetic factors that typically affect drug metabolism or clearance. To verify the relevance and
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A phase I drug–drug interaction study to assess the effect of futibatinib on P‐gp and BCRP substrates and of P‐gp inhibition on the pharmacokinetics of futibatinib Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-11 Amanda Long, Ikuo Yamamiya, Michelle Valentine, Ziv Machnes, Nanae Hangai, Bailey Anderson, Volker Wacheck, Ling Gao
Futibatinib, an inhibitor of fibroblast growth factor receptor 1–4, is approved for the treatment of patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements. In this phase I drug–drug interaction study, the effects of futibatinib on P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) substrates, and of P‐gp inhibition on futibatinib pharmacokinetics (PK) were investigated
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Randomized, placebo‐controlled study on the effects of intravenous GSK3858279 (anti‐CCL17) on a battery of evoked pain tests in healthy participants Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-09 Yvonne Boyle, Hemme J. Hijma, Jamie Rees, Jagtar Nijjar, Eirini Panoilia, Yolanda Alvarez, Sarah Siederer, Emma Greening, Edward Emery, Kathy Abbott Banner, Geert Jan Groeneveld
C–C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G‐protein coupled CC‐chemokine receptor 4 and has been implicated in the development of inflammatory and arthritic pain. GSK3858279 is a high‐affinity, first‐in‐class, monoclonal antibody, binding specifically to CCL17 and inhibiting downstream signaling. In this phase I, randomized, single‐center, double‐blind
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Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-04 Hengbang Wang, Yun Yang, Zi Chen, Lei Fu, Min Yu, Lixin Jiang, Cunlin Wang, Lichuang Men, Ilisse Minto, Dajun Yang, Yifan Zhai
Olverembatinib (HQP1351) is a BCR‐ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug‐resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics
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Explainable machine learning prediction of edema adverse events in patients treated with tepotinib Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-02 Federico Amato, Rainer Strotmann, Roberto Castello, Rolf Bruns, Vishal Ghori, Andreas Johne, Karin Berghoff, Karthik Venkatakrishnan, Nadia Terranova
Tepotinib is approved for the treatment of patients with non‐small‐cell lung cancer harboring MET exon 14 skipping alterations. While edema is the most prevalent adverse event (AE) and a known class effect of MET inhibitors including tepotinib, there is still limited understanding about the factors contributing to its occurrence. Herein, we apply machine learning (ML)‐based approaches to predict the
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Randomized, double-blind, phase 1a single-ascending dose and food effect studies assessing safety and pharmacokinetics of EC5026 in healthy volunteers. Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-01 William K Schmidt,Irene Cortés-Puch,Cindy B McReynolds,Glenn E Croston,Sung Hee Hwang,Jun Yang,Theresa L Pedersen,Karen M Wagner,Theresa T Pham,Thomas Hunt,Bruce D Hammock
Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety
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Computational drug discovery pipelines identify NAMPT as a therapeutic target in neuroendocrine prostate cancer. Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-09-01 Weijie Zhang,Adam Lee,Lauren Lee,Scott M Dehm,R Stephanie Huang
Neuroendocrine prostate cancer (NEPC) is an aggressive advanced subtype of prostate cancer that exhibits poor prognosis and broad resistance to therapies. Currently, few treatment options are available, highlighting a need for new therapeutics to help curb the high mortality rates of this disease. We designed a comprehensive drug discovery pipeline that quickly generates drug candidates ready to be
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Low‐gainer diet‐induced obese microbiota transplanted mice exhibit increased fighting Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-30 Caroline M. Junker Mentzel, Yan Hui, Tanja Maria Stentoft Hammerich, Malene Klug‐Dambmann, Yi Liu, Line Fisker Zachariassen, Lars Hestbjerg Hansen, Antonios Aslampaloglou, Maria Kiersgaard, Dennis Sandris Nielsen, Axel Kornerup Hansen, Lukasz Krych
Weight gain variation is a great challenge in diet‐induced obesity studies since low‐gainer animals are of limited experimental value. The inbred C57BL/6 (B6) mice are frequently used models due to their genetic homogeneity and susceptibility to diet‐induced obesity (DIO). The aim of this study is to investigate if the gut microbiota (GM) influences the fraction of low weight gainers in DIO studies
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From organs to algorithms: Redefining cancer classification in the age of artificial intelligence Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-29 Sean Khozin
Traditional cancer classification based on organ of origin and histology is increasingly at odds with precision oncology. Tumors in different organs can share molecular features, while those in the same organ can be heterogeneous. This disconnect impacts clinical trials, drug development, and patient care. Recent advances in artificial intelligence (AI), particularly machine learning and deep learning
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Patterns of pharmacogenetic variation in nine biogeographic groups Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-29 Sophia Hernandez, Lucia A. Hindorff, Joannella Morales, Erin M. Ramos, Teri A. Manolio
Frequencies of pharmacogenetic (PGx) variants are known to differ substantially across populations but much of the available PGx literature focuses on one or a few population groups, often defined in nonstandardized ways, or on a specific gene or variant. Guidelines produced by the Clinical Pharmacogenetic Implementation Consortium (CPIC) provide consistent methods of literature extraction, curation
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MB09, a denosumab biosimilar candidate: Biosimilarity demonstration in a phase I study in healthy subjects Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-29 Monika Tomaszewska‐Kiecana, Elisabete Carapuça, Amalia Florez‐Igual, Javier Queiruga‐Parada
This was a Phase I, randomized, double‐blinded, three‐arm, single‐dose, parallel study aimed to demonstrate pharmacokinetic (PK) similarity between MB09 (a denosumab biosimilar candidate) and reference denosumab (XGEVA® from European Union [EU‐reference] and United States [US‐reference]) in a healthy male population. The primary PK endpoints included: Area under the serum concentration versus time
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Lexicon for blood‐based early detection and screening: BLOODPAC consensus document Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-29 Christina A. Clarke, Breeana L. Mitchell, Girish Putcha, Emma Alme, Peter Bach, Jonathan P. Beer, Tomasz M. Beer, Michelle A. Beidelschies, Jody Hoyos, Eric Klein, Peter Kuhn, Nancy Krunic, Kathryn Lang, Jerry S. H. Lee, Dorys Lopez Ramos, David Morgenstern, Elissa Quinn, Victoria M. Raymond, Wendy S. Rubinstein, Stephanie A. Sanchez, Ryan Serra, Mark Stewart, Lauren C. Leiman
In the United States, 2.0 million new cancer cases and around 600,000 cancer deaths are estimated to occur in 2024. Early detection gives cancer patients the best chance for treatment success. Currently, cancer screening in the general population is recommended for a limited set of cancers; as a result, most cancer types are not regularly screened. Thus, in recent years, we have seen a wave of novel
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Momelotinib: Mechanism of action, clinical, and translational science Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-27 Georgios Vlasakakis, Michael T. McCabe, Yu Liu Ho, Geraldine Ferron‐Brady, Paul Martin, Darren Bentley, Catherine Ellis, Mary Antonysamy, Sandra A. G. Visser
Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related anemia, a negative prognostic factor for survival
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Novel cathepsin C inhibitor, BI 1291583, intended for treatment of bronchiectasis: Phase I characterization in healthy volunteers Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-23 Philipp Badorrek, Claudia Diefenbach, Harald Kögler, Anastasia Eleftheraki, Friedeborg Seitz, Jens M. Hohlfeld
Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil‐derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI
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Pharmacokinetics, pharmacodynamics, and safety of GS‐3583, a FLT3 agonist Fc fusion protein, from single‐ascending‐dose phase I study in healthy participants Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-22 Anees M. Dauki, Nishanthan Rajakumaraswamy, Torsten Trowe, Winnie Weng, Kai‐Wen Lin, Emon Elboudjwarej, Ann Ran‐Ran Qin, Christian Schwabe, Michelle R. Kuhne, Ahmed A. Othman
Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor‐specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms‐like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to
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Predicting progression‐free survival from measurable residual disease in chronic lymphocytic leukemia Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-22 Florencia A. Tettamanti, Holly Kimko, Shringi Sharma, Giovanni Di Veroli
Association between measurable residual disease (MRD) and survival outcomes in chronic lymphocytic leukemia (CLL) has often been reported. However, limited quantitative analyses over large datasets have been undertaken to establish the predictive power of MRD. Here, we provide a comprehensive assessment of published MRD data to explore the utility of MRD in the prediction of progression‐free survival
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Reply to “A call for reporting of tumor‐specific outcomes in studies of DPYD genotyping” Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-22 Nihal El Rouby, Josiah D. Allen, Megan Muldoon, Mollie Beck, Kristina Hesse, Nichlas Sebree, Robin Yoder, Stacey Ritter, Zuhair Alqahtani, Jaime Grund, Brooke Philips Holbrook
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Expression and prognostic potential of osteopontin splice variants in malignant melanoma Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-17 Gabriela Ribeiro Silva, Luciana Bueno Ferreira, Etel Rodrigues Pereira Gimba
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Dose‐dependent induction of CYP3A activity by St. John's wort alone and in combination with rifampin Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-17 Nicolas Hohmann, Anna S. Friedrichs, Jürgen Burhenne, Antje Blank, Gerd Mikus, Walter E. Haefeli
The dose dependence of the effect of enzyme inducers and the effect of the combined administration of two inducers that exert their effect via the same induction pathway (pregnane X receptor) have not been well studied. Using oral midazolam microdoses (30 μg), we have investigated CYP3A4 induction by St. John's wort (SJW) in 11 healthy volunteers using low (300 mg/day containing 7.48 mg hyperforin)
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First‐in‐human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-17 Hidetoshi Shimizu, Michael A. Tortorici, Yoshiyasu Ohta, Kei Ogawa, Sheikh Mohammed Ashfaq Rahman, Aya Fujii, Yuki Hiraga, Mizue Kawai, Kanami Sugimoto‐Kawabata, Mattheus (Thijs) van Iersel, Jan Jaap van Lier, Stephen Djedjos, B. T. Slingsby, David M. Rodman
Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β‐hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone‐dependent, uncontrolled hypertension, including treatment‐resistant hypertension
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Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry – Informing optimal antiplatelet strategies Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-16 Larisa H. Cavallari, Craig R. Lee, Francesco Franchi, Ellen C. Keeley, Joseph S. Rossi, Cameron D. Thomas, Yan Gong, Caitrin W. McDonough, Petr Starostik, Maryam J. Al Saeed, Latonya Been, Natasha Kulick, Jean Malave, Ian R. Mulrenin, Anh B. Nguyen, Joshua N. Terrell, Grace Tillotson, Amber L. Beitelshees, Almut G. Winterstein, George A. Stouffer, Dominick J. Angiolillo
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no‐function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown
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MVP enhances FGF21‐induced ferroptosis in hepatocellular carcinoma by increasing lipid peroxidation through regulation of NOX4 Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-15 Jinkun Xia, Boqi Fu, Zhe Wang, Gaolin Wen, Quanshui Gu, Dayu Chen, Haozhen Ren
Ferroptosis is a novel, iron‐dependent regulatory cell death mainly caused by an imbalance between the production and degradation of intracellular reactive oxygen species (ROS). Recently, ferroptosis induction has been considered a potential therapeutic approach for hepatocellular carcinoma (HCC). Fibroblast growth factor 21 (FGF21) is a new modulator of ferroptosis; however, the regulatory role of
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Benchmarking pharmacogenomics genotyping tools: Performance analysis on short‐read sequencing samples and depth‐dependent evaluation Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-10 Andreas Halman, Sebastian Lunke, Simon Sadedin, Claire Moore, Rachel Conyers
Pharmacogenomics (PGx) investigates the influence of genetics on drug responses, enabling tailored treatments for personalized healthcare. This study assessed the accuracy of genotyping six genes using whole genome sequencing with four different computational tools and various sequencing depths. The effects of using different reference genomes (GRCh38 and GRCh37) and sequence aligners (BWA‐MEM and
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Functional differences in the mu opioid receptor SNP 118A>G are dependent on receptor splice‐variant and agonist‐specific recruitment of β‐arrestin Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-09 Casey Patrick, Utibeabasi Ettah, Vu Nguyen, Caitlin Hart, Evan Atchley, Krishna Mallela, Robert I. Scheinman, Andrew A. Monte
The OPRM1 gene codes for the mu opioid receptor (MOR) and polymorphisms are associated with complex patient clinical responses. The most studied single nucleotide polymorphism (SNP) in OPRM1 is adenine (A) substituted by guanine (G) at position 118 (118A>G, rs1799971) leading to a substitution of asparagine (Asn) for aspartic acid (Asp) at position 40 in the N terminus of the resulting protein. To
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Using exploratory pharmacokinetic and pharmacodynamic analyses to predict the probability of flu‐like symptoms in healthy volunteers and patients with chronic hepatitis B treated with the toll‐like receptor 7 agonist ruzotolimod Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-09 Qiudi Jiang, Yuchen Zhang, Dan Duan, Sylvie Retout, Ruchi Upmanyu, Katerina Glavini, Miriam Triyatni, Yonghong Zhu, Joseph F. Grippo, Yuyan Jin
Ruzotolimod (Toll‐like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno‐modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug‐related adverse events of flu‐like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic
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Regulation of exosomes as biologic medicines: Regulatory challenges faced in exosome development and manufacturing processes Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-08 Chun‐Kai Wang, Teng‐Huang Tsai, Chung‐Hsi Lee
With advances in medical technology, extracellular vesicles, also known as exosomes, are gaining widespread attention because of their potential therapeutic applications. However, their regulatory landscape is complex and varies across countries because of their unique intracellular mechanisms of action. The diversity of manufacturing techniques renders their standardization challenging, leading to
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Exploring the discrepancies between clinical trials and real‐world data: A small‐cell lung cancer study Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-08 Luca Marzano, Adam S. Darwich, Asaf Dan, Salomon Tendler, Rolf Lewensohn, Luigi De Petris, Jayanth Raghothama, Sebastiaan Meijer
The potential of real‐world data to inform clinical trial design and supplement control arms has gained much interest in recent years. The most common approach relies on reproducing control arm outcomes by matching real‐world patient cohorts to clinical trial baseline populations. However, recent studies pointed out that there is a lack of replicability, generalisability, and consensus. In this article
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Early administration of ketorolac after cardiac surgery and postoperative complications: Analysis of the MIMIC‐IV database Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-05 Yi Liu, Bo Pan, Jie Liu, Jun Zhang
Inflammation may contribute to postoperative cardiac complications and ketorolac, an anti‐inflammatory agent inhibiting cyclooxygenase (COX), shows promise in enhancing cardiac graft patency by suppressing endothelial cell proliferation in animal studies. However, the safety of postoperative ketorolac use remains controversial. This study investigates the association between early ketorolac application
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A case study of inclusion of rural populations in research: Implications for science and health equity Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-02 Devon Noonan, Wendy K. K. Lam, James Goodrich, Sydney Sullivan, Keisha Bentley‐Edwards, Dwight Koeberl, Anushka Palipana, F. Joseph McClernon
Prior research highlights that rural populations have been historically underrepresented/excluded from clinical research. The primary objective of this study was to describe the inclusion of rural populations within our research enterprise using Clinical Research Management System demographic information at a large academic medical center in the Southeast. This was a cross‐sectional study using participant
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Real‐world evidence to support regulatory submissions: A landscape review and assessment of use cases Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-02 Golnoosh Alipour‐Haris, Xinyue Liu, Virginia Acha, Almut G. Winterstein, Mehmet Burcu
Real‐world evidence (RWE) has an increasing role in preapproval settings to support the approval of new medicines and indications. The main objectives of this study were to identify and characterize regulatory use cases that utilized RWE and other related observational approaches through targeted review of publications and regulatory review documents. After screening and inclusion/exclusion, the review
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Challenges with sirolimus experimental data to inform QSP model of post-transplantation cyclophosphamide regimens. Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-01 Ezhilpavai Mohanan,Guofang Shen,Suping Ren,Hsuan-Hao Fan,Kao Tang Ying Moua,Aleksandra Karolak,Russell C Rockne,Ryotaro Nakamura,David A Horne,Christopher G Kanakry,Donald E Mager,Jeannine S McCune
Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important
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A call for reporting of tumor-specific outcomes in studies of DPYD genotyping. Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-08-01 Jean De Dieu Ndayishimiye,Mari Cayabyab,Glenda Hoffecker,Victoria Wittner,,Sony Tuteja
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Dupilumab: Mechanism of action, clinical, and translational science Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-31 Marc R. McCann, Matthew P. Kosloski, Christine Xu, John D. Davis, Mohamed A. Kamal
Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)‐4 receptor alpha subunit (IL‐4Rα) that blocks IL‐4 and IL‐13 signaling
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Pharmacokinetics, pharmacodynamics, and safety of asundexian in healthy Chinese and Japanese volunteers, and comparison with Caucasian data Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-31 Huijun Chen, Kensei Hashizume, Friederike Kanefendt, Christine Brase, Sebastian Schmitz, Tianxing Liu
There is an unmet clinical need for effective anticoagulant therapies for the management of thromboembolic diseases that are not associated with a relevant risk of bleeding. Asundexian (BAY 2433334) is an oral, direct, small‐molecule inhibitor of activated factor XI (FXIa). Phase I data from healthy Caucasian male participants indicated predictable pharmacokinetic (PK) and pharmacodynamic (PD) profiles
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Feasibility and accuracy of mobile QT interval monitoring strategies in bedaquiline‐enhanced prophylactic leprosy treatment Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-30 Auke T. Bergeman, Said Nourdine, Alberto Piubello, Zahara Salim, Sofie M. Braet, Abdallah Baco, Silahi H. Grillone, Rian Snijders, Carolien Hoof, Achilleas Tsoumanis, Harry van Loen, Younoussa Assoumani, Aboubacar Mzembaba, Nimer Ortuño‐Gutiérrez, Epco Hasker, Christian van der Werf, Bouke C. de Jong
Some anti‐mycobacterial drugs are known to cause QT interval prolongation, potentially leading to life‐threatening ventricular arrhythmia. However, the highest leprosy and tuberculosis burden occurs in settings where electrocardiographic monitoring is challenging. The feasibility and accuracy of alternative strategies, such as the use of automated measurements or a mobile electrocardiogram (mECG) device
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Pharmacogenomics polygenic risk score: Ready or not for prime time? Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-30 Sonal Singh, Gabriele Stocco, Katherine N. Theken, Alyson Dickson, QiPing Feng, Jason H. Karnes, Jonathan D. Mosley, Nihal El Rouby
Pharmacogenomic Polygenic Risk Scores (PRS) have emerged as a tool to address the polygenic nature of pharmacogenetic phenotypes, increasing the potential to predict drug response. Most pharmacogenomic PRS have been extrapolated from disease‐associated variants identified by genome wide association studies (GWAS), although some have begun to utilize genetic variants from pharmacogenomic GWAS. As pharmacogenomic
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Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate‐to‐severe atopic dermatitis: Results from two terminated phase II trials Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-30 Matthew P. Kosloski, Emma Guttman‐Yassky, Michael J. Cork, Margitta Worm, Dong‐Ho Nahm, Xiaoping Zhu, Marcella K. Ruddy, Sivan Harel, Mohamed A. Kamal, Hélène Goulaouic, Christine R. Xu, Elena Avetisova, John D. Davis, Michael C. Nivens, Arsalan Shabbir, Allen Radin
Interleukin‐33 (IL‐33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL‐33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL‐33, currently in clinical development
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Drug–drug interactions between pemafibrate and statins on pharmacokinetics in healthy male volunteers: Open‐label, randomized, 6‐sequence, 3‐period crossover studies Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-30 Tomohiro Kamimura, Neil Hounslow, Hideki Suganami, Ryohei Tanigawa
Elevated triglyceride levels are associated with an increased risk of cardiovascular events despite guideline‐based statin treatment of low‐density lipoprotein cholesterol. Peroxisome proliferator‐activated receptor α (PPARα) agonists exert a significant triglyceride‐lowering effect. However, combination therapy of PPARα agonists with statins poses an increased risk of rhabdomyolysis, which is rare
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Assessing the net financial benefits of employing digital endpoints in clinical trials Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-29 Joseph A. DiMasi, Abigail Dirks, Zachary Smith, Sarah Valentine, Jennifer C. Goldsack, Thomas Metcalfe, Upinder Grewal, Lada Leyens, Ute Conradi, Daniel Karlin, Lesley Maloney, Kenneth A. Getz, Bert Hartog
In the last few decades, developers of new drugs, biologics, and devices have increasingly leveraged digital health technologies (DHTs) to assess clinical trial digital endpoints. To our knowledge, a comprehensive assessment of the financial net benefits of digital endpoints in clinical trials has not been conducted. We obtained data from the Digital Medicine Society (DiMe) Library of Digital Endpoints
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Translational pharmacokinetic/pharmacodynamic model for mRNA‐0184, an investigational therapeutic for the treatment of heart failure Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-27 Neeraj Kaushal, Husain Attarwala, Mir Javid Iqbal, Rajnish Saini, Linh Van, Min Liang
Heart failure (HF) is a complex, progressive disorder that is associated with substantial morbidity and mortality on a global scale. Relaxin‐2 is a naturally occurring hormone that may have potential therapeutic benefit for patients with HF. To investigate the therapeutic potential of relaxin in the treatment of patients with HF, mRNA‐0184, a novel, investigational, lipid nanoparticle (LNP)–encapsulated
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Ascites affects the benefit of carvedilol on patients with liver cirrhosis and esophageal and gastric varices Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-25 Ruiqi Xia, Bing Wu, Ji Zhou, Mingyan Ji, Shuyue Wang, Xiaoqing Zeng, Shiyao Chen
Esophageal and gastric varices (EGV) bleeding is a dangerous side effect of liver cirrhosis. Ascites may affect the effectiveness of carvedilol in preventing EGV rebleeding. A retrospective analysis was done on patients with EGV bleeding who visited our gastroenterology department between January 1, 2015, and October 29, 2020, and were given carvedilol therapy again. Patients were classified based
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Implementation of a pharmacogenetic panel‐based test for pharmacotherapy‐based supportive care in an adult oncology clinic Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-24 Emily J. Cicali, Elizabeth Eddy, Yan Gong, Amanda L. Elchynski, Kim Pena del Aguila, Tala Basha, Karen C. Daily, Lauren Dickson, Steven Fischer, Erin Hastings‐Monari, Dennie Jones, Brian H. Ramnaraign, David L. DeRemer, Thomas J. George, Rhonda M. Cooper‐DeHoff
The University of Florida Health conducted a pragmatic implementation of a pharmacogenetics (PGx) panel‐based test to guide medications used for supportive care prescribed to patients undergoing chemotherapy. The implementation was in the context of a pragmatic clinical trial for patients with non‐hematologic cancers being treated with chemotherapy. Patients were randomized to either the intervention
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Parkinson's disease: Still waiting for a cure Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-24 D. Kevin Kwok
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Generalizability in real‐world trials Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-24 Anatol‐Fiete Näher, Marvin Kopka, Felix Balzer, Matthias Schulte‐Althoff
Real‐world evidence (RWE) trials have a key advantage over conventional randomized controlled trials (RCTs) due to their potentially better generalizability. High generalizability of study results facilitates new biological insights and enables targeted therapeutic strategies. Random sampling of RWE trial participants is regarded as the gold standard for generalizability. Additionally, the use of sample
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Increasing acceptance of AI‐generated digital twins through clinical trial applications Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-23 Anna A. Vidovszky, Charles K. Fisher, Anton D. Loukianov, Aaron M. Smith, Eric W. Tramel, Jonathan R. Walsh, Jessica L. Ross
Today's approach to medicine requires extensive trial and error to determine the proper treatment path for each patient. While many fields have benefited from technological breakthroughs in computer science, such as artificial intelligence (AI), the task of developing effective treatments is actually getting slower and more costly. With the increased availability of rich historical datasets from previous
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Pharmacokinetic drug–drug interactions of JBPOS0101 mediated by cytochrome P450 3A4 and UDP‐glucuronosyltransferases Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-22 Sejung Hwang, Yong Moon Choi, Myoung‐Seok Kim, SeungHwan Lee
JBPOS0101 is a new antiepileptic drug and is a substrate of UDP‐glucuronosyltransferases (UGTs) in in vitro test. In vitro experiments showed different results regarding whether JBPOS0101 induces (EC50 136 μM) or inhibits (IC50 95.4–386.5 μM) cytochrome P450 (CYP) 3A4. As co‐medication of JBPOS0101 and carbamazepine (CBZ) is expected in clinical settings, drug–drug interactions (DDIs) between them
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PBPK‐led assessment of antimalarial drugs as candidates for Covid‐19: Simulating concentrations at the site of action to inform repurposing strategies Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-18 Nada Abla, Lisa M. Almond, Jennifer J. Bonner, Naomi Richardson, Timothy N. C. Wells, Jörg J. Möhrle
The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID‐19) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). In vitro activity does not always translate to clinical
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How debunking biases in research and development decisions could lead to more equitable healthcare? Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-17 Benjamin Weber, Issam Zineh, Richard Lalonde, Sandra A. G. Visser
Decades of research have demonstrated that a variety of cognitive biases can affect our judgment and ability to make rational decisions in personal and professional environments. The lengthy, risky, and costly nature of pharmaceutical research and development (R&D) makes it vulnerable to biased decision‐making. Moreover, cognitive biases can play a role in regulatory and clinical decision‐making, the
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Reduced hepatic impairment study to evaluate pharmacokinetics and safety of zavegepant and to inform dosing recommendation for hepatic impairment Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-17 Rajinder Bhardwaj, Mary K. Donohue, Jennifer Madonia, Beth Morris, Thomas C. Marbury, Kyle T. Matschke, Robert Croop, Richard Bertz, Jing Liu
Zavegepant, a high‐affinity, selective, small‐molecule calcitonin gene‐related peptide (CGRP) receptor antagonist, is approved in the United States for acute treatment of migraine in adults. The effects of moderate hepatic impairment (8 participants with Child‐Pugh score 7–9 points) on the pharmacokinetics of a single 10‐mg intranasal dose of zavegepant versus eight matched participants with normal
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Pharmacokinetics and safety of mavacamten in healthy Chinese participants with different CYP2C19 phenotypes Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-17 Xiaojie Wu, Nanye Chen, Peiwen Hsu, Jing Sun, Wenting Li, Qi Wang, Merali Samira, Qiong Wei, Jicheng Yu, Guoying Cao, Haijing Yang, Lili Wang, Jingjing Wang, Yi Jin, Wei Liu, Jufang Wu, Jinjie He, Cheng Lyu, Jing Zhang
Obstructive hypertrophic cardiomyopathy (oHCM) is a subtype of HCM characterized by left ventricular outflow tract obstruction resulting from cardiac muscle hypertrophy and anatomic alterations in the mitral valve and apparatus. Mavacamten, a cardiac myosin inhibitor metabolized primarily by CYP2C19 in the liver, is the first and only targeted medication approved for the treatment of symptomatic New
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Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-16 Sylvia D. Klomp, Anette Veringa, Jan‐Willem C. Alffenaar, Mark G. J. de Boer, Lambert F. R. Span, Henk‐Jan Guchelaar, Jesse J. Swen
Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the
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The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first‐in‐class ACKR3/CXCR7 antagonist, ACT‐1004‐1239 Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-16 Christine Huynh, Jasper Dingemanse, Henriette E. Meyer zu Schwabedissen, Marlene Fonseca, Patricia N. Sidharta
Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug–drug interactions (DDIs). ACT‐1004‐1239 is a potent and selective, first‐in‐class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism,
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Pharmacokinetics of Sofosbuvir/Velpatasvir and efficacy of an alternate‐day treatment in hemodialysis patients with chronic hepatitis C infection Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-15 Pajaree Chariyavilaskul, Nantaporn Prompila, Supeecha Wittayalertpanya, Sookruethai Lekhyananda, Wisit Prasithsirikul, Thananda Trakarnvanich, Somboon Jeenapongsa, Paweena Susantitaphong, Stephen Kerr, Anchalee Avihingsanon, Pisit Tangkijvanich, Kearkiat Praditpornsilpa
Sofosbuvir/Velpatasvir (SOF/VEL) is a combination drug used for chronic hepatitis C (HCV) infection. However, limited information exists regarding the pharmacokinetics of SOF/VEL and its metabolites in hemodialysis patients. We conducted a prospective investigation of the pharmacokinetic parameters of SOF/VEL after a single dose of SOF/VEL (400/100 mg) on days with and without dialysis in 12 Thai hemodialysis
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Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States: A comparative study of accelerated approvals Clin. Transl. Sci. (IF 3.1) Pub Date : 2024-07-11 Hayase Hakariya, Frank Moriarty, Akihiko Ozaki, Shai Mulinari, Hiroaki Saito, Tetsuya Tanimoto
Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross‐sectional study, we considered 23