Cts-Clinical and Translational Science最新文献

{"title":"Inter-Ethnic Differences in the Efficacy and Safety of Tyrosine Kinase Inhibitors Used in Oncology: Insights From Phase 3 Clinical Trials","authors":"Nicki M. Kyriacou,&nbsp;Annette S. Gross,&nbsp;Andrew J. McLachlan","doi":"10.1111/cts.70224","DOIUrl":"https://doi.org/10.1111/cts.70224","url":null,"abstract":"<p>Differences in the efficacy and safety of tyrosine kinase inhibitors (TKIs) have been observed across ethnic/ancestry subpopulations (previously reviewed to 2017). With an expanding number of TKIs approved since that time, an updated review of TKI response across ethnic/ancestry subpopulations in Phase 3 TKI clinical trials was conducted. A total of 73 population subgroup analyses (defined by participant race, ethnicity, ancestry or geographic region) of progression-free survival (PFS) and/or overall survival (OS) were identified by a literature search. Twelve (16%) of the analyses investigating the efficacy of afatinib, brigatinib, dacomitinib, gilteritinib, lorlatinib, neratinib, osimertinib, or pazopanib were assessed to report population differences in PFS and/or OS. For 28 (38%) of the analyses that showed suggestions of a potential efficacy difference across subpopulations, limitations in the data available precluded further assessment. There were 17 (23%) analyses assessed to report comparable efficacy outcomes across diverse subpopulations. The majority of clinical trials noted no clinically remarkable differences in safety between subpopulations; however, for brigatinib, crizotinib, pazopanib, and sunitinib, distinct patterns of adverse events were reported in the Asian and non-Asian subgroups. The underrepresentation of specific subpopulations, the grouping together of results of diverse subpopulations, as well as inconsistencies in the definition and reporting of participant ethnicity/ancestry are barriers to the meaningful exploration of inter-ethnic differences in TKI response. Therefore, further insight into the associations between ethnicity/ancestry and TKI response will require an increase in the diversity of clinical trial participants and appropriate analysis and reporting of subpopulation results.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883956","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":"Low Dose Methotrexate Has Divergent Effects on Cycling and Resting Human Hematopoietic Stem and Progenitor Cells","authors":"Maximilien Lora,&nbsp;H. A. Ménard,&nbsp;Anastasia Nijnik,&nbsp;David Langlais,&nbsp;Marie Hudson,&nbsp;Inés Colmegna","doi":"10.1111/cts.70233","DOIUrl":"https://doi.org/10.1111/cts.70233","url":null,"abstract":"<p>Low dose methotrexate (LD-MTX) remains the gold standard in rheumatoid arthritis (RA) therapy. Multiple mechanisms on a variety of immune cells contribute to the anti-inflammatory effects of LD-MTX. Inflammatory signaling is deeply implicated in hematopoiesis by regulating hematopoietic stem and progenitor cell (HSPC) fate decisions; raising the question of whether HSPC are also modulated by LD-MTX. This is the first study to characterize the effects of LD-MTX on HSPC. CD34⁺ HSPC were isolated from healthy donors' non-mobilized peripheral blood. Resting and/or cycling HSPCs were treated with LD-MTX [dose equivalent to that used in RA patients]. Flow cytometry was performed to assess HSPC viability, cell cycle, surface abundance of reduced folate carrier 1 (RFC1), proliferation, reactive oxygen species (ROS) levels, DNA double-strand breaks, p38 activation, and CD34⁺ subpopulations. HSPC clonogenicity was tested in colony-forming cell assays. Our results indicate that in cycling HSPC, membrane RFC1 is upregulated and, following LD-MTX treatment, they accumulate more intracellular MTX than resting HSPC. In cycling HSPC, LD-MTX inhibits HSPC expansion by promoting S-phase cell-cycle arrest, increases intracellular HSPC ROS levels and DNA damage, and reduces HSPC viability. Those effects involve the activation of the p38 MAPK pathway and are rescued by folinic acid. The effects of LD-MTX are more evident in CD34⁺ CD38High progenitors. In non-cycling HSPC, LD-MTX also reduces the proliferative response while preserving their clonogenicity. In summary, HSPC uptake LD-MTX differentially according to their cycling state. In turn, LD-MTX results in reduced proliferation and the preservation of HSPC clonogenicity.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70233","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879857","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":"Experimental Insights and Recommendations for Successfully Performing Cerebral Microdialysis With Hydrophobic Drug Candidates","authors":"Julia K. Sundheimer,&nbsp;Julia Benzel,&nbsp;Rémi Longuespée,&nbsp;Jürgen Burhenne,&nbsp;Stefan M. Pfister,&nbsp;Kendra K. Maaß,&nbsp;Max Sauter,&nbsp;Kristian W. Pajtler","doi":"10.1111/cts.70226","DOIUrl":"https://doi.org/10.1111/cts.70226","url":null,"abstract":"<p>Cerebral microdialysis in rodents represents a robust and versatile technique for quantifying the pharmacologically relevant unbound fraction of drugs in the brain. When this unbound fraction is simultaneously determined in plasma, it facilitates the calculation of the corresponding unbound plasma-to-brain partition coefficient (K_p,uu) for a given compound in vivo. This coefficient is critical for understanding the penetration and distribution of drugs across the blood–brain barrier (BBB). However, obtaining valid and accurate microdialysis data can be particularly challenging for hydrophobic drugs due to their pronounced non-specific interactions with the components of the microdialysis system. The present study reports the outcomes of comprehensive microdialysis investigations in rodents, focusing on three hydrophobic compounds: actinomycin D, selinexor, and ulixertinib. These compounds exhibited varying degrees of non-specific binding to the surfaces of the microdialysis apparatus, leading to low recovery rates and substantial carry-over effects. To diminish these limitations, strategies such as surface coating and the use of optimized materials were employed to enhance the reliability of the microdialysis system. To ensure the robustness and reproducibility of microdialysis-related research outcomes, our experimental findings were supplemented with a narrative literature review. This review encompassed keyword-driven PubMed-indexed publications on microdialysis from 1970 to 2024, providing a broader context for the challenges and solutions associated with the technique. By integrating empirical results with practical recommendations, this study offers a comprehensive resource aimed at advancing the application of cerebral microdialysis in preclinical drug development, particularly for compounds with challenging physicochemical properties.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877836","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":"Alternative Dosing Regimens of Tislelizumab Using a Pharmacometrics Model-Based Approach","authors":"Ahsan Rizwan,&nbsp;Hugh Giovinazzo,&nbsp;Tian Yu,&nbsp;Yuying Gao,&nbsp;Kun Wang,&nbsp;Fengyan Xu,&nbsp;Ya Wan,&nbsp;Jun Wang,&nbsp;Srikumar Sahasranaman,&nbsp;Marcia Campbell,&nbsp;Patrick Schnell,&nbsp;Ramil Abdrashitov,&nbsp;William D. Hanley,&nbsp;Nageshwar Budha","doi":"10.1111/cts.70223","DOIUrl":"https://doi.org/10.1111/cts.70223","url":null,"abstract":"<p>Tislelizumab 200 mg once every 3 weeks (Q3W) is approved for the treatment of multiple cancers. We used a model-based approach to propose three alternative dosing regimens, 150 mg Q2W, 300 mg Q4W, and 400 mg Q6W, with the aims of providing flexible treatment regimens compatible with background chemotherapy and/or reducing infusion visits. A previously developed population pharmacokinetic model was used to simulate pharmacokinetic exposure of the alternative regimens. Regulatory guidance on alternative dosing was used to define pharmacokinetics-based criteria. Alternative doses were selected by simulation, exposure matching, and comparison to the reference regimen of 200 mg Q3W. Deviations from pharmacokinetics-based criteria were bridged using appropriate safety and efficacy references and exposure–response analyses. All three alternative dosing regimens produced comparable exposures versus 200 mg Q3W. Although simulated peak serum concentration (C_max) at 300 mg Q4W and 400 mg Q6W was higher versus 200 mg Q3W, this was below the C_max of the 5 mg/kg Q3W safety reference. And while the trough serum concentration (C_trough) for 400 mg Q6W was slightly lower versus 200 mg Q3W, it was 10.7% higher than the 2 mg/kg efficacy reference C_trough, and therefore, within the concentration range in which a flat exposure–efficacy relationship of tislelizumab has been established. Tislelizumab regimens of 150 mg Q2W, 300 mg Q4W, and 400 mg Q6W are expected to result in similar safety and efficacy as 200 mg Q3W.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877835","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":"Clinical Pharmacology Overview of Tislelizumab in Patients With Advanced Tumors With a Focus on Racial Impact","authors":"Tian Yu,&nbsp;Chi-Yuan Wu,&nbsp;Srikumar Sahasranaman,&nbsp;Xianbin Tian,&nbsp;Ying Fei Li,&nbsp;Zhiyu Tang,&nbsp;Yanfei Yang,&nbsp;Ya Wan,&nbsp;Quting Zhang,&nbsp;Patrick Schnell,&nbsp;Ariadna Mendoza-Naranjo,&nbsp;Ramil Abdrashitov,&nbsp;William D. Hanley,&nbsp;Nageshwar Budha","doi":"10.1111/cts.70221","DOIUrl":"https://doi.org/10.1111/cts.70221","url":null,"abstract":"<p>Tislelizumab, an anti-programmed cell death protein-1 monoclonal antibody, has demonstrated improved survival over the standard of care for multiple cancers. However, tislelizumab's effectiveness across different racial/ethnicity groups warrants further evaluation. This clinical pharmacology overview includes tislelizumab's pharmacokinetic properties, correlations with efficacy and safety, and immunogenicity, with a focus on racial impact. Non-compartmental pharmacokinetic analysis was conducted using data from Asian and White patients enrolled in BGB-A317-001 and BGB-A317-102. Population pharmacokinetic analyses used pooled data from 12 clinical studies to evaluate the impact of intrinsic/extrinsic factors on tislelizumab's pharmacokinetic properties, including race effect. Exposure–efficacy/exposure–safety relationships and immunogenicity assessments were evaluated for the phase III BGB-A317-302/-303 studies. Tislelizumab exhibited dose-proportional pharmacokinetics, and there were no clinically meaningful differences in tislelizumab's pharmacokinetic parameters at 200 mg once every 3 weeks between BGB-A317-001 (<i>n</i> = 12, 83% White patients) and BGB-A317-102 (<i>n</i> = 20, 100% Chinese patients); race was not a significant covariate. No clinically relevant exposure–efficacy/−safety relationships were observed in BGB-A317-302/-303. Incidence of anti-drug antibodies (ADAs) was similar between Asian and White patients. The presence of ADAs was not clinically relevant for tislelizumab's pharmacokinetic properties, efficacy, or safety. There were no differences in tislelizumab's pharmacokinetic or ADA characteristics between Asian and White patients with advanced cancer and no clinically relevant exposure–efficacy/−safety dependency or impact of immunogenicity on efficacy and safety. Data from the extensive clinical program of tislelizumab support the use of tislelizumab across broad patient populations with relevant tumor types.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877834","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":"Evaluation of DOAC Dosing Among Various Renal Equations in Patients With Kidney Impairment and Elderly in Thailand","authors":"Sayamon Sukkha,&nbsp;Supatat Chumnumwat,&nbsp;Pattaranun Thongsoi,&nbsp;Rawiphon Sonsiri,&nbsp;Apisara Lohachatinante,&nbsp;Nuttanun Kittikunkanyakit,&nbsp;Rattana Chawanasuntharapot,&nbsp;Junporn Kongwatcharapong","doi":"10.1111/cts.70238","DOIUrl":"https://doi.org/10.1111/cts.70238","url":null,"abstract":"<p>The Thai Food and Drug Administration (TFDA) has approved direct oral anticoagulant (DOAC) dosing based on estimated creatinine clearance, eCrCl (Cockcroft-Gault equation). However, other renal function equations are often used in practice for patients with kidney disease, leading to potential discrepancies in DOAC dosing recommendations. The actual DOAC dosing patterns in resource-limited countries remain underreported. This cross-sectional study included patients with renal impairment who were treated at the outpatient department of Siriraj Hospital, Mahidol University, Thailand. Patients received their first DOAC for atrial fibrillation from January 2019 to December 2022. The primary objective was to evaluate the percentage of DOAC prescriptions compliant with TFDA guidelines using eCrCl. We also examined dosing agreement when substituting estimated glomerular filtration rate, eGFR (CKD-EPI) for eCrCl. Patient factors and the incidence of stroke and bleeding over a one-year follow-up were also assessed. A total of 326 patients and 1587 DOAC prescriptions were analyzed. The mean patient age was 79.1 ± 9.2 years, with a mean eGFR of 45.6 ± 9.9 mL/min/1.73 m². TFDA-compliant dosing was observed in 68.2% of prescriptions. Dose disagreement between eGFR and eCrCl was 45%, with a trend toward overdosing using eGFR. An eGFR of less than 45 mL/min/1.73 m² was associated with dose discrepancies. Stroke and bleeding incidences were low, with no differences across DOAC types. While most Thai patients received appropriate DOAC dosing, one-third did not comply with TFDA guidelines. Using eGFR instead of eCrCl may result in dosing differences, particularly in moderate to severe renal impairment.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875603","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 Beta-Blocker Pharmacogenetic Puzzle: More Pieces of Evidence for Pharmacodynamic Candidate Variants","authors":"Jasmine A. Luzum,&nbsp;Shana D. R. Littleton,&nbsp;Ana I. Lopez-Medina,&nbsp;Bin Liu,&nbsp;Ruicong She,&nbsp;David E. Lanfear","doi":"10.1111/cts.70239","DOIUrl":"https://doi.org/10.1111/cts.70239","url":null,"abstract":"<p>Previous pharmacogenetic findings for beta-blocker pharmacodynamic candidate genes (<i>ADRB1</i>, <i>ADRB2</i>, <i>ADRA2C, GRK4,</i> and <i>GRK5)</i> have been inconsistent. Therefore, the purpose of this study was to determine whether interactions of pharmacodynamic variants with beta-blocker exposure significantly associated with survival in patients with heart failure with reduced ejection (HFrEF). The 893 patients were 51% self-reported African American and 49% self-reported White race, 36% female, and 240 died (27%) over a median follow-up of 2.8 years. The primary outcome was all-cause mortality. Using Cox proportional hazards models with time-varying beta-blocker exposure and adjusted for clinical risk factors and ancestry, interactions of <i>ADRB1</i> Arg389Gly, <i>ADRB1</i> Ser49-Arg389Gly haplotype, <i>ADRA2C</i> Del_322-325, and <i>GRK4</i> Ala486Val with beta-blocker exposure were significant before correction for multiple comparisons (<i>p</i> &lt; 0.1), but only <i>GRK4</i> Ala486Val remained significant in African Americans after correction for multiple comparisons using the adaptive Hochberg method (<i>p</i> = 0.022). Beta-blocker exposure only associated with a significant reduction in the risk of mortality in the African American HFrEF patients with the <i>GRK4</i> Ala486/Ala486 genotype (HR = 0.44; 95% CI = 0.20–0.96; <i>p</i> = 0.04). In conclusion, the interaction of <i>GRK4</i> Ala486Val with beta-blocker exposure significantly associated with survival in African American HFrEF patients. Larger sample sizes or meta-analyses are needed to have more statistical power to better assess beta-blocker pharmacogenetic interactions for <i>ADRB1</i> Arg389Gly, <i>ADRB1</i> Ser49-Arg389Gly haplotype, and <i>ADRA2C</i> Del_322-325 in the future.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875621","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":"Development of an Ancestrally Inclusive Preemptive Pharmacogenetic Testing Panel","authors":"Christelle Lteif,&nbsp;Brian E. Gawronski,&nbsp;Emily J. Cicali,&nbsp;Katherine A. Martinez,&nbsp;Kimberly J. Newsom,&nbsp;Petr Starostik,&nbsp;Larisa H. Cavallari,&nbsp;Julio D. Duarte","doi":"10.1111/cts.70230","DOIUrl":"https://doi.org/10.1111/cts.70230","url":null,"abstract":"<p>Pharmacogenetic (PGx) testing can individualize pharmacotherapy, but many current panels lack inclusivity for diverse populations and are often cost-prohibitive for medically underserved communities. This study aimed to develop and validate GatorPGx Plus, a low-cost, preemptive PGx panel tailored for diverse patient populations. Pharmacogenes were selected based on the drug/drug classes potentially influenced by their variants, the clinical severity of drug-gene interactions, or the strength of guideline recommendations or emerging evidence. Variants within the pharmacogenes were included if their allele frequencies were approximately 1% or greater in any major ancestral population. The panel was validated for accuracy, precision, and analytical sensitivity and applied to 124 participants from an ongoing pharmacogenetic clinical implementation trial. To reduce costs, a high-throughput platform was chosen, laboratory technician hands-on time was minimized, and result translation and reporting were automated. The panel comprised tests for 62 variants in 14 genes/gene regions, including a <i>CYP2D6</i> copy number assay. It demonstrated 100% concordance with reference methods. The average turnaround time between test order and results was 14.3 (±6.4) days. Among the 124 genotyped trial participants (mean age 60 years, 57.3% female), 99% had at least one non-normal function (less common or higher-risk) phenotype. The most frequently identified non-normal function phenotypes were in <i>CYP2C19</i> (69.4%). <i>CYP2D6 *17</i>, <i>*29</i>, and <i>CYP2C19 *9</i> were captured at higher frequencies than reported in European populations. GatorPGx Plus is a low per-test cost, clinically validated, preemptive PGx panel that effectively captures key variants in a mixed-ancestry population, underscoring its potential clinical utility in diverse, medically underserved populations.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875643","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":"Bioequivalence and Food Effect Assessment of Two Fixed-Dose Combination Formulations of Telmisartan-Hydrochlorothiazide Tablets in Chinese Healthy Subjects","authors":"Minwan Hu,&nbsp;Man Yang,&nbsp;Shuyu Zhang,&nbsp;Jiangfan Li,&nbsp;Hongxian Pang,&nbsp;Yingzi Pei,&nbsp;Chao Guo,&nbsp;Xuhong Wang","doi":"10.1111/cts.70228","DOIUrl":"https://doi.org/10.1111/cts.70228","url":null,"abstract":"<p>This study assessed the bioequivalence and food effect of two fixed-dose combination (FDC) formulations of telmisartan-hydrochlorothiazide tablets (telmisartan 40 mg, hydrochlorothiazide 12.5 mg) in healthy Chinese subjects. Seventy-two subjects were enrolled and divided into fasted and fed cohorts in a single-center, randomized, open-label, single-dose, three-period, three-sequence, and crossover study. The pharmacokinetic characteristics of telmisartan and hydrochlorothiazide, including C_max and AUC, were compared after subjects received single oral doses of telmisartan-hydrochlorothiazide tablets using a validated LC–MS/MS method. Safety and tolerability of treatments were monitored. Pharmacokinetic profiles of two FDC telmisartan-hydrochlorothiazide tablets were comparable after single-dose administration. 90% CI of geometric mean ratios (GMRs) of AUC_0-t, AUC_0-∞, and C_max of telmisartan and hydrochlorothiazide of two FDC formulations fell within the predefined bioequivalence range of 80.0%–125.0% under both fasted and fed conditions. Administration with food had significant effects on telmisartan pharmacokinetic parameters but a slight impact on hydrochlorothiazide. Notably, C_max and AUC of telmisartan were significantly decreased by 39.6%–43.7% in the fed versus fasted conditions. Safety assessments revealed all treatments were safe and well tolerated. Two telmisartan-hydrochlorothiazide FDC formulations were bioequivalent in healthy Chinese subjects in both fasted and fed states. All treatments were well tolerated.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875644","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":"Ethnic Sensitivity Assessment of Mosunetuzumab Pharmacokinetics and Pharmacodynamics in Chinese Patients With Relapsed or Refractory Follicular Lymphoma","authors":"Junyi Li,&nbsp;Michael Z. Liao,&nbsp;Justin Wilkins,&nbsp;Elicia Penuel,&nbsp;Bei Wang,&nbsp;Shweta Vadhavkar,&nbsp;Kun Peng,&nbsp;Junning Cao,&nbsp;Zhiming Li,&nbsp;Ye Zhang,&nbsp;Wenjin Li,&nbsp;Donghang Li,&nbsp;Mingzhu Zhou,&nbsp;Michael C. Wei,&nbsp;Antonia Kwan,&nbsp;Rong Zhao,&nbsp;Chunze Li,&nbsp;Chi-Chung Li,&nbsp;David C. Turner","doi":"10.1111/cts.70211","DOIUrl":"https://doi.org/10.1111/cts.70211","url":null,"abstract":"<p>Mosunetuzumab, a CD20 × CD3 T-cell-engaging bispecific antibody, redirects T cells to eliminate malignant B cells. The purpose of YO43555 was to assess the pharmacokinetics (PK), safety, tolerability, and efficacy of mosunetuzumab as a single agent in Chinese patients with relapsed/refractory follicular lymphoma (R/R FL). The impact of ethnicity/region on the PK disposition of mosunetuzumab was assessed by non-compartmental analysis (NCA) as well as a population PK (popPK) approach. A previously established popPK model for intravenous mosunetuzumab, built from the global Phase I/II study GO29781, was externally validated with the PK data from study YO43555. Results from the PK analysis showed that the global popPK model adequately captured the individual PK of the Chinese population. The model predicted mosunetuzumab exposure metrics in Chinese patients were similar to those observed in Asian patients in the GO29781 R/R FL subpopulation with the same dose regimen, while the exposure differences between Chinese and Non-Asians from the global population were &lt; 20%. An overlay of the exposure levels for Chinese patients on the established E-R relationship in global patients indicated that the mosunetuzumab exposure of Chinese patients remained within the established bounds for clinical safety and efficacy. The cytokine biomarkers IL-6 and TNF-α showed similar time-course patterns of release as observed in globally enrolled patients. In summary, mosunetuzumab PK disposition did not show significant ethnic sensitivity that would impact patient outcomes. Therefore, dose adjustment of the globally approved mosunetuzumab regimen is not warranted for Chinese patients with R/R FL.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT02500407</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875622","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}