Cts-Clinical and Translational Science最新文献

{"title":"Population Pharmacokinetic–Pharmacodynamic Modeling of Granulocyte Colony-Stimulating Factor to Optimize Dosing and Timing for CD34+ Cell Harvesting","authors":"Xu Jiang,&nbsp;Jun Seok Cha,&nbsp;Byung Hak Jin,&nbsp;Choon Ok Kim,&nbsp;Dongwoo Chae","doi":"10.1111/cts.70121","DOIUrl":"10.1111/cts.70121","url":null,"abstract":"<p>Granulocyte colony-stimulating factor (G-CSF) mobilizes peripheral blood (PB) progenitor cells from bone marrow (BM) into circulation for PB stem cell transplantation (PBSCT). This study aimed to develop a population pharmacokinetic–pharmacodynamic (PK-PD) model of filgrastim in healthy subjects to optimize PB CD34⁺ cell collection. Plasma filgrastim concentrations and CD34⁺ cell count data were obtained from a clinical study involving healthy Korean subjects. A total of 1378 plasma concentration measurements and 982 CD34⁺ cell count data collected from 53 subjects were used in the PK-PD model. Filgrastim PKs were adequately described by a one-compartment linear disposition model with an additional transit compartment for absorption. Log-transformed body weight was the only significant covariate affecting the volume of distribution and clearance. CD34⁺ cell mobilization was best captured by a modified Friberg model, assuming continual entry of proliferating BM stem cells into PB via a single transit compartment. Simulation results suggested that the 5 μg/kg twice-daily dosing regimen may yield higher CD34⁺ cell counts compared to the 10 μg/kg once-daily regimen for achieving target CD34⁺ cell counts of 20/μL and 50/μL. We successfully developed a robust PK-PD model of G-CSF that optimizes the yield of CD34⁺ cells during allogeneic PBSCT. This model can guide the efficient determination of optimal G-CSF dosing regimens and CD34⁺ cell harvesting strategies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923484","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 randomized, double-blind, placebo-controlled, multiple dose, parallel study to investigate the effects of a cathepsin S inhibitor in celiac disease","authors":"Darren Bentley,&nbsp;Marie Mannino,&nbsp;Marianne Manchester,&nbsp;Priscila Camillo Teixeira,&nbsp;Bernhard Reis,&nbsp;Malcolm Boyce,&nbsp;Sandra Nagel","doi":"10.1111/cts.13901","DOIUrl":"10.1111/cts.13901","url":null,"abstract":"<p>Celiac disease is a chronic, immune-mediated enteropathy with symptoms triggered by exposure to dietary gluten in genetically predisposed individuals. The only available management option is lifelong adherence to a gluten-free diet. This randomized, double-blind, placebo-controlled, parallel-group, single-center study tested the effects of the cathepsin S inhibitor RO5459072 on the immune response to a 13-day gluten challenge in 19 participants with celiac disease (ClinicalTrials.gov: NCT02679014). Nine participants in the RO5459072 arm received 100 mg study drug b.i.d. (200 mg daily); 10 received a placebo. The primary end point was the number of responders to the gluten challenge (defined as individuals with an increase in the number of gliadin-specific, IFNγ-secreting T cells detected using an ELISPOT assay). However, there was a weak response to the gluten challenge across both arms. Few participants had an increase in gliadin-specific, IFNγ-secreting T cells, and the antigen-specific responses (anti-tTG and anti-DGP antibodies) were weaker than expected in both arms. Therefore, the primary end point was not met, although the study was underpowered to detect a treatment effect under these circumstances. Pharmacodynamic findings suggested that RO5459072 had some beneficial effects. Fewer participants in the RO5459072 arm exhibited gliadin-specific IFNγ-secreting T cells after 6 days' gluten intake. Participants in the RO5459072 arm also showed decreased intestinal permeability, and a decrease in the number of circulating B cells, CD4+ and CD8+ T cells compared to baseline. Nevertheless, the absence of clear effects on the response to a gluten challenge indicates that inhibition of cathepsin S may not be an effective treatment strategy for celiac disease.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911061","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":"Rapid identification and phenotyping of nonalcoholic fatty liver disease patients using a machine-based approach in diverse healthcare systems","authors":"Anna O. Basile,&nbsp;Anurag Verma,&nbsp;Leigh Anne Tang,&nbsp;Marina Serper,&nbsp;Andrew Scanga,&nbsp;Ava Farrell,&nbsp;Brittney Destin,&nbsp;Rotonya M. Carr,&nbsp;Anuli Anyanwu-Ofili,&nbsp;Gunaretnam Rajagopal,&nbsp;Abraham Krikhely,&nbsp;Marc Bessler,&nbsp;Muredach P. Reilly,&nbsp;Marylyn D. Ritchie,&nbsp;Nicholas P. Tatonetti,&nbsp;Julia Wattacheril","doi":"10.1111/cts.70105","DOIUrl":"10.1111/cts.70105","url":null,"abstract":"<p>Nonalcoholic fatty liver disease (NAFLD) is the most common global cause of chronic liver disease and remains under-recognized within healthcare systems. Therapeutic interventions are rapidly advancing for its inflammatory phenotype, nonalcoholic steatohepatitis (NASH) at all stages of disease. Diagnosis codes alone fail to recognize and stratify at-risk patients accurately. Our work aims to rapidly identify NAFLD patients within large electronic health record (EHR) databases for automated stratification and targeted intervention based on clinically relevant phenotypes. We present a rule-based phenotyping algorithm for efficient identification of NAFLD patients developed using EHRs from 6.4 million patients at Columbia University Irving Medical Center (CUIMC) and validated at two independent healthcare centers. The algorithm uses the Observational Medical Outcomes Partnership (OMOP) Common Data Model and queries structured and unstructured data elements, including diagnosis codes, laboratory measurements, and radiology and pathology modalities. Our approach identified 16,006 CUIMC NAFLD patients, 10,753 (67%) previously unidentifiable by NAFLD diagnosis codes. Fibrosis scoring on patients without histology identified 943 subjects with scores indicative of advanced fibrosis (FIB-4, APRI, NAFLD–FS). The algorithm was validated at two independent healthcare systems, University of Pennsylvania Health System (UPHS) and Vanderbilt Medical Center (VUMC), where 20,779 and 19,575 NAFLD patients were identified, respectively. Clinical chart review identified a high positive predictive value (PPV) across all healthcare systems: 91% at CUIMC, 75% at UPHS, and 85% at VUMC, and a sensitivity of 79.6%. Our rule-based algorithm provides an accurate, automated approach for rapidly identifying, stratifying, and sub-phenotyping NAFLD patients within a large EHR system.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911006","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 phase I, randomized, placebo-controlled trial to evaluate the pharmacokinetics, safety, and tolerability of nirsevimab in healthy Chinese adults","authors":"Xiaomeng Mao,&nbsp;Xiaohan Hua,&nbsp;Chengyi Wu,&nbsp;Xiaoyun Ge,&nbsp;Jie Zhang,&nbsp;Xiaojie Wu,&nbsp;Robert J. Kubiak,&nbsp;Ulrika Wählby Hamrén,&nbsp;Tonya Villafana,&nbsp;Georgios Christou,&nbsp;Jannine Green,&nbsp;Therese Takas,&nbsp;Yuwen Jin","doi":"10.1111/cts.70095","DOIUrl":"10.1111/cts.70095","url":null,"abstract":"<p>Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in infants worldwide. Nirsevimab, an extended half-life monoclonal antibody against RSV, is approved in China for the prevention of RSV lower respiratory tract disease in infants; however, global nirsevimab trials did not enroll Chinese infants. To inform the investigation of nirsevimab for the prevention of RSV LRTI in Chinese infants, this Phase I, randomized, placebo-controlled trial evaluated the pharmacokinetics (PK) and safety of nirsevimab in healthy Chinese adults. Participants were randomized 3:1 to a single 300 mg intramuscular dose of nirsevimab or placebo and were followed through 150 days post-dose. Serum nirsevimab concentrations were measured and PK parameters of maximum serum concentration (<i>C</i>_max), time to maximum concentration (<i>t</i>_max), and area under the concentration-time curve from time 0 to Day 150 (AUC_0–150) were estimated. Treatment emergent adverse events (AEs), clinical laboratory data, and vital signs were evaluated. Overall, 24 participants were randomized to nirsevimab (<i>n</i> = 18) or placebo (<i>n</i> = 6). Nirsevimab geometric mean (coefficient of variation [%CV]) <i>C</i>_max was 46.9 (21.7) μg/mL, median (range) <i>t</i>_max was 7.0 (4.9, 29.9) days, and geometric mean (%CV) AUC_0–150 was 4210.6 (13.6) μg·day/mL. Treatment-emergent AEs (all Grade 1 or Grade 2 in severity) were reported in 5/18 (27.8%) nirsevimab recipients and 2/6 (33.3%) placebo recipients. No serious AEs, new onset chronic disease, or deaths were reported. Overall, safety and PK outcomes were consistent with those observed in healthy adults in the USA, with no new safety concerns.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907904","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":"With big data comes big responsibility: Strategies for utilizing aggregated, standardized, de-identified electronic health record data for research","authors":"Veronica R. Olaker,&nbsp;Sarah Fry,&nbsp;Pauline Terebuh,&nbsp;Pamela B. Davis,&nbsp;Daniel J. Tisch,&nbsp;Rong Xu,&nbsp;Margaret G. Miller,&nbsp;Ian Dorney,&nbsp;Matvey B. Palchuk,&nbsp;David C. Kaelber","doi":"10.1111/cts.70093","DOIUrl":"10.1111/cts.70093","url":null,"abstract":"<p>Electronic health records (EHRs), though they are maintained and utilized for clinical and billing purposes, may provide a wealth of information for research. Currently, sources are available that offer insight into the health histories of well over a quarter of a billion people. Their use, however, is fraught with hazards, including introduction or reinforcement of biases, clarity of disease definitions, protection of patient privacy, definitions of covariates or confounders, accuracy of medication usage compared with prescriptions, the need to introduce other data sources such as vaccination or death records and the ensuing potential for inaccuracy, duplicative records, and understanding and interpreting the outcomes of data queries. On the other hand, the possibility of study of rare disorders or the ability to link apparently disparate events are extremely valuable. Strategies for avoiding the worst pitfalls and hewing to conservative interpretations are essential. This article summarizes many of the approaches that have been used to avoid the most common pitfalls and extract the maximum information from aggregated, standardized, and de-identified EHR data. This article describes 26 topics broken into three major areas: (1) 14 topics related to design issues for observational study using EHR data, (2) 7 topics related to analysis issues when analyzing EHR data, and (3) 5 topics related to reporting studies using EHR data.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11685181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911008","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":"Safety and Phosphate-Binding Capacity of Oxylanthanum Carbonate in Healthy Volunteers","authors":"Pablo E. Pergola,&nbsp;Melanie S. Joy,&nbsp;Armando Garsd,&nbsp;Steve J. Hasal,&nbsp;Atul Khare,&nbsp;Guru Reddy,&nbsp;Pramod Gupta,&nbsp;William F. Finn","doi":"10.1111/cts.70116","DOIUrl":"10.1111/cts.70116","url":null,"abstract":"<p>Despite the widespread use of currently available serum phosphate management options, elevated serum phosphate is common in patients with end-stage kidney disease on dialysis. Characteristics of currently available phosphate binders that lead to poor patient experiences such as large drug volume size of required daily medication (e.g., many large tablets) and adverse gastrointestinal effects may decrease compliance to labeled dosing instructions, thus decreasing their efficacy. Oxylanthanum carbonate is a new molecule yielding the same phosphate-binding capacity as lanthanum carbonate, but in a much smaller drug volume and tablet size. It is formulated as small tablets that can be easily swallowed. In a double-blind dose-escalation phase 1 study, healthy volunteers (<i>n</i> = 32) were randomly divided into four treatment arms and randomly assigned to receive oxylanthanum carbonate tablets or a placebo over a period of 4 days to evaluate safety, urinary and fecal excretion of phosphorus, and pharmacokinetics. Each treatment arm evaluated a different dose of oxylanthanum carbonate: 500, 1000, 1500, or 2000 mg three times a day (TID). The study drug was well-tolerated. Oxylanthanum carbonate effectively decreased dietary phosphorus absorption, demonstrated by decreased urinary phosphorus excretion and increased fecal phosphorus excretion. Systemic absorption of oxylanthanum carbonate was minimal, with lanthanum serum concentration values below the level of quantification (0.500 ng/mL) in all subjects receiving 500 mg TID and did not exceed 0.7 ng/mL at other doses. Future studies should evaluate and confirm the ability of oxylanthanum carbonate to reduce pill burden and improve dose administration, patient tolerability, adherence, and treatment outcomes.</p><p>\u0000 <b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT01560884</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11672196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900163","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":"Predicting the exposure of mycophenolic acid in children with autoimmune diseases using a limited sampling strategy: A retrospective study","authors":"Ping Zheng,&nbsp;Ting Pan,&nbsp;Ya Gao,&nbsp;Juan Chen,&nbsp;Liren Li,&nbsp;Yan Chen,&nbsp;Dandan Fang,&nbsp;Xuechun Li,&nbsp;Fei Gao,&nbsp;Yilei Li","doi":"10.1111/cts.70092","DOIUrl":"10.1111/cts.70092","url":null,"abstract":"<p>Mycophenolic acid (MPA) is commonly used to treat autoimmune diseases in children, and therapeutic drug monitoring is recommended to ensure adequate drug exposure. However, multiple blood sampling is required to calculate the area under the plasma concentration-time curve (AUC), causing patient discomfort and waste of human and financial resources. This study aims to use machine learning and deep learning algorithms to develop a prediction model of MPA exposure for pediatric autoimmune diseases with optimizing sampling frequency. Pediatric autoimmune patients' data were collected at Nanfang Hospital between June 2018 and June 2023. Univariate analysis was applied for feature selection. Ten algorithms, including Random Forest, XGBoost, LightGBM, Gradient Boosting Decision Tree, CatBoost, Artificial Neural Network, Grandient Boosting Machine, Transformer, Wide&amp;Deep, and TabNet, were employed for modeling based on two, three, or four concentrations of MPA. A total of 614 MPA AUC_0-12h samples from 209 patients were enrolled. Among the 10 models evaluated, the Wide&amp;Deep model exhibited the best predictive performance. The predictive performance of the Wide&amp;Deep model using four and three blood concentration points was similar (<i>R</i>\u0000 ² ≈ 1 for four points; <i>R</i>\u0000 ² = 0.95 for three points). No significant difference in accuracy within ±30% was observed between models utilizing three and four blood concentration points (<i>p</i> = 0.06). This study demonstrates that in the Wide&amp;Deep model, MPA exposure can be accurately estimated with three sampling points in children with autoimmune diseases. This model could help reduce discomfort in pediatric patients without reducing the accuracy of MPA exposure estimates in clinical practice.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11672284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900162","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":"Population pharmacokinetics of iruplinalkib in healthy volunteers and patients with solid tumors","authors":"Guihong Yang,&nbsp;Yimei Wang,&nbsp;Huimin Zhao,&nbsp;Ziyi Jiang,&nbsp;Shansong Zheng,&nbsp;Mingjing Ge,&nbsp;Meimei Si,&nbsp;Xiaoyan Kang","doi":"10.1111/cts.70099","DOIUrl":"10.1111/cts.70099","url":null,"abstract":"<p>Iruplinalkib (WX-0593), a selective oral ALK/ROS1 tyrosine kinase inhibitor, was approved in China as first-line therapy for <i>ALK</i>-positive non-small-cell lung cancer (NSCLC) and for the treatment of locally advanced or metastatic <i>ALK</i>-positive NSCLC that has progressed following crizotinib therapy. Pharmacokinetics (PK) data of iruplinalkib have been collected in healthy subjects and patient populations in several studies. We developed a population PK (PopPK) model for describing iruplinalkib plasma concentrations and for evaluating whether dose adjustments are necessary based on demographic factors or disease characteristics. Plasma concentration–time data were collected from 392 participants (16 healthy volunteers and 372 patients with solid tumors) who received single or multiple doses of iruplinalkib in four trials. Data were analyzed using non-linear mixed-effects modeling. Iruplinalkib plasma concentrations were best described by a two-compartment model with first-order absorption and first-order elimination. Baseline body weight, time-varying albumin, time-varying creatinine clearance, and time-varying lactate dehydrogenase were significant covariates of apparent clearance from the central compartment (CL/<i>F</i>) while baseline body weight was a significant covariate of apparent volume of the central compartment (V1/<i>F</i>). Given the small or modest effect of all statistically significant covariates on iruplinalkib exposure at steady-state, no covariate was expected to have clinically meaningful effects on iruplinalkib exposure. Furthermore, iruplinalkib absorption was delayed 0.472 h after meal, and <i>K</i>_a was 58.8% of that under fasting. However, there was no difference in exposure of iruplinalkib between the fasted and fed states. In conclusion, the PopPK model adequately describes iruplinalkib PK properties in Chinese healthy subjects and patients with solid tumors. No covariate had a clinically meaningful impact on iruplinalkib exposure. These results indicate that dose adjustment of iruplinalkib is not necessary, based on the aforementioned covariates, for ALK-positive NSCLC patients.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900161","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":"Safety of BI 1358894 in patients with major depressive disorder: Results and learnings from a phase II randomized decentralized clinical trial","authors":"Christopher Reist,&nbsp;Peide Li,&nbsp;Thuy Le Nguyen,&nbsp;Sigurd D. Süssmuth","doi":"10.1111/cts.70102","DOIUrl":"10.1111/cts.70102","url":null,"abstract":"<p>The feasibility of conducting a fully remote, interventional, phase II decentralized clinical trial (DCT) was investigated in major depressive disorder (MDD). Key learnings were collated to improve future DCTs. A double-blind, placebo-controlled, parallel-group, DCT enrolled adult MDD patients with inadequate response to first-line antidepressant monotherapy (ongoing ≥8 weeks) and a Montgomery-Åsberg Depression Rating Scale total score (MADRS) ≥22 at screening. Patients were randomized 1:1 to BI 1358894 125 mg or placebo daily for 6 weeks remotely. Safety parameters, primary end point (change from baseline in MADRS at Week 6), and patient experience were assessed. The DCT was considered feasible if the trial protocol could be successfully executed. Overall, DCT procedures were successfully executed per protocol. However, despite achieving a vast patient outreach, the trial was terminated early due to deficient enrollment. Of the 136 patients who consented for enrollment and underwent screening, 45 were randomized and 43 received treatment (BI 1358894, <i>n</i> = 20; placebo, <i>n</i> = 23); 97.7% of patients completed the trial. Patients had a mean (SD) age of 42.2 (13.1) years and most (83.7%) were female. Adverse events were reported by 86.0% of patients (BI 1358894, 90.0%; placebo, 82.6%). Most patients (88%) reported a positive experience with the DCT. Key learnings related to the impact of stringent eligibility criteria, recruitment optimization strategies, plus the benefits and limitations of digital technologies. A fully remote, interventional DCT was feasible in MDD, and was well perceived by trial participants. Learnings related to recruitment optimization and trial design should be considered for future interventional DCTs.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883158","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, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase I study","authors":"Nanyang Li,&nbsp;Nannan Chu,&nbsp;Leilei Zhu,&nbsp;Xiaojie Wu,&nbsp;Qiong Wei,&nbsp;Jiahui Wang,&nbsp;Xuhui Hu,&nbsp;Haoyu Yu,&nbsp;Qingyu Wang,&nbsp;Wei'an Yuan,&nbsp;Kai Huang,&nbsp;Jing Zhang","doi":"10.1111/cts.70089","DOIUrl":"https://doi.org/10.1111/cts.70089","url":null,"abstract":"<p>Denosumab is a human IgG2 monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) for the treatment of osteoporosis and bone loss. HLX14 is a proposed biosimilar of denosumab. This randomized, parallel-group, two-part, phase I study aimed to compare the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 with reference denosumab in Chinese healthy adult male participants. In Part 1, participants were randomized 1:1 and given HLX14 or reference denosumab sourced from the European Union (EU). In double-blind Part 2, participants were randomized 1:1:1:1 to receive HLX14 or denosumab sourced from the United States, EU, or China. All study drugs were administered via subcutaneous injection at a single dose of 60 mg. The primary endpoints were area under the serum drug concentration–time curve from time 0 to the last concentration-quantifiable time <i>t</i> (AUC_0–t), maximum serum drug concentration (<i>C</i>_max), and area under the serum drug concentration–time curve from time 0 to infinity (AUC_0–inf). Twenty-four participants were randomized in Part 1 and 228 in Part 2. The 90% confidence intervals of geometric mean ratio of AUC_0–<i>t</i>, <i>C</i>_max, and AUC_0–inf between HLX14 and denosumab from different sources fell within the pre-specified similarity margins of 0.80–1.25 (AUC_0–<i>t</i>, 0.91–1.13; <i>C</i>_max, 0.91–1.13; AUC_0–inf, 0.91–1.12), demonstrating pharmacokinetic similarity. No notable difference was observed among treatment groups in pharmacodynamics, safety, or immunogenicity. HLX14 demonstrated highly similar pharmacokinetic characteristics with comparable pharmacodynamics, safety, and immunogenicity to denosumab, supporting its further investigation as a potential denosumab biosimilar.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861680","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}