Cts-Clinical and Translational Science最新文献

{"title":"Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INT-787, a Novel Farnesoid X Receptor Agonist, in Healthy Volunteers: A Phase 1 Trial","authors":"Thomas Capozza,&nbsp;Jennifer Burkey,&nbsp;Jeroen Van De Wetering,&nbsp;Reinhold Kerb,&nbsp;Jennifer Callahan,&nbsp;Ludmila Kryzhanovskaya,&nbsp;Mary Erickson","doi":"10.1111/cts.70229","DOIUrl":"https://doi.org/10.1111/cts.70229","url":null,"abstract":"<p>Aberrant farnesoid X receptor (FXR) signaling is implicated in cholestatic, inflammatory, and fibrotic liver diseases. In preclinical/clinical studies, semisynthetic bile acid-derived FXR agonists markedly improved hepatic function in various conditions. INT-787, a novel hydrophilic semisynthetic bile acid FXR agonist, has demonstrated a reduction in inflammatory and fibrotic markers and regulation of bile acid/lipid metabolism. This first-in-human, randomized, placebo-controlled phase 1 study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of INT-787 and its equipotent metabolites in healthy volunteers by evaluating single ascending doses (SAD), multiple ascending doses (MAD), and food effect. Participants (<i>n</i> = 130) across all study portions were similar in age, race, and body mass index. In the SAD and MAD portions, the maximum plasma concentration (<i>C</i>_max) and area under the curve (AUC) for total INT-787 generally increased with dose. In the Food Effect portion, the mean <i>C</i>_max of total INT-787 was almost 2-fold higher under fasted conditions compared with fed conditions; AUC_0-inf was unchanged. Steady state for total INT-787 was reached by Day 7. In cohorts receiving ≥ 50 mg doses, the half-life of total INT-787 ranged from 21 to 55 h. INT-787 metabolites exhibited increased concentrations after mealtimes despite morning dosing, consistent with endogenous bile acid behavior. Following single and multiple doses of INT-787, decreases in C4 and increases in FGF-19 levels were observed. Single and multiple oral doses were generally well tolerated; 4 adverse events of mild, transient pruritus not requiring interventions were reported at higher doses. These results warrant further investigation of INT-787 in patients with liver-related disorders.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889017","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":"Impacts of Pharmacokinetic Gene Polymorphisms on Steady-State Plasma Concentrations of Simvastatin in Thai Population","authors":"Sayanit Tipnoppanon,&nbsp;Udomsak Udomnilobol,&nbsp;Sarawut Siwamogsatham,&nbsp;Yongkasem Vorasettakarnkij,&nbsp;Chonlaphat Sukasem,&nbsp;Thomayant Prueksaritanont,&nbsp;Pajaree Chariyavilaskul,&nbsp;Varalee Yodsurang,&nbsp;Thanate Srimatimanon,&nbsp;Monpat Chamnanphon,&nbsp;Natchaya Vanwong","doi":"10.1111/cts.70225","DOIUrl":"https://doi.org/10.1111/cts.70225","url":null,"abstract":"<p>Simvastatin, an HMG-CoA reductase inhibitor, is widely used for hypercholesterolemia but may cause myotoxicity linked to its plasma concentration. Pharmacokinetic gene polymorphisms influence inter-individual variability in simvastatin exposure. This study investigated the effects of pharmacokinetic gene polymorphisms on steady-state simvastatin plasma levels in Thai patients. Eighty-nine Thai patients with dyslipidemia or coronary artery disease on simvastatin treatment for at least 2 weeks without dose adjustment were recruited from King Chulalongkorn Memorial Hospital. Simvastatin lactone and acid concentrations were measured 12 h post-dose using UHPLC–MS/MS. Pharmacokinetic gene polymorphisms, including <i>ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, CYP3A4,</i> and <i>CYP3A5</i>, were genotyped by MassARRAY System. The results showed that patients with the <i>SLCO1B1</i> c.521TC+CC genotype had significantly higher simvastatin acid levels than those with c.521TT (0.53 vs. 0.19 ng/mL, <i>p</i> = 0.03). Similarly, the <i>SLCO1B1</i>*<i>1b/</i>*<i>15</i> genotype was associated with higher simvastatin acid levels than <i>SLCO1B1</i>*<i>1a</i>/*<i>1a</i> (0.58 vs. 0.16 ng/mL, <i>p</i> &lt; 0.001). These findings suggest that <i>SLCO1B1</i> c.521T&gt;C, alone or with c.388A&gt;G (<i>SLCO1B1</i>*<i>1b/</i>*<i>15</i>), reduces OATP1B1 function, leading to elevated simvastatin acid levels and increased myotoxicity risk. This study confirms the association of <i>SLCO1B1</i> rs4149056 (c.521T&gt;C) with higher simvastatin plasma levels in Thai patients. The study highlights the potential role of <i>SLCO1B1</i> genotyping, particularly rs4149056 (c.521T&gt;C) and rs2306283 (c.388A&gt;G), in guiding statin therapy for Thai patients, which could help optimize treatment and reduce adverse effects such as statin-induced myotoxicity.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884073","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":"EDP-323, a First-In-Class, Once-Daily, Oral L-Protein Inhibitor for the Treatment of RSV: Results From a Phase 1 Study in Healthy Adults","authors":"Kimberly Elmore,&nbsp;John DeVincenzo,&nbsp;Michael H. J. Rhodin,&nbsp;Scott T. Rottinghaus,&nbsp;Alaa Ahmad","doi":"10.1111/cts.70231","DOIUrl":"https://doi.org/10.1111/cts.70231","url":null,"abstract":"<p>Respiratory syncytial virus (RSV) remains a significant health concern, particularly for vulnerable populations. Despite preventive strategies, there remains a need for effective antiviral treatments. EDP-323 is a first-in-class, potent oral selective non-nucleoside inhibitor of the large protein (L polymerase) of RSV under investigation for the treatment of RSV infection. This phase 1, randomized, double-blind, placebo-controlled study evaluated the safety and pharmacokinetics of EDP-323. This study included fasted single ascending dose (SAD; EDP-323 50/100/200/400/600/800 mg doses, 3:1 to placebo), fed multiple ascending dose (MAD; EDP-323200/400/600/800 mg doses, 3:1 to placebo), and food effect (EDP-323200 mg dose, 4:1 to placebo) cohorts in healthy adult participants. Key objectives were to assess the safety, tolerability, and pharmacokinetic (PK) profile of EDP-323 in plasma and urine, and to evaluate the effect of food intake on its pharmacokinetics. Among 82 randomized participants (SAD, <i>n</i> = 50; MAD, <i>n</i> = 32), EDP-323 was well tolerated up to the highest tested dose (800 mg once daily for 7 days). Adverse events (AEs) were reported in 14.6% of total participants, with the majority being mild and deemed unlikely related to the study drug. Headache was the most frequent AE (<i>n</i> = 3). PK analysis showed that EDP-323 was rapidly absorbed (<i>T</i>_max = 3.0–5.0 h), with exposures increasing with ascending dose. The half-life of EDP-323 (<i>t</i>_1/2 = 10.8–16.6 h) supported once-daily dosing, and no food effect was observed. EDP-323 demonstrated a favorable safety and PK profile, supporting its potential as a once-daily oral treatment for RSV.</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.70231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879952","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 and Testing of the Protocol Quality Rating Tool (PQRT) to Evaluate Clinical Trial Protocol Document Quality","authors":"Angela K. Lyden,&nbsp;Claire Z. Kalpakjian,&nbsp;Cathie Spino,&nbsp;Susan L. Murphy,&nbsp;Julie C. Lumeng,&nbsp;Anna S. Lok","doi":"10.1111/cts.70240","DOIUrl":"https://doi.org/10.1111/cts.70240","url":null,"abstract":"<p>A high-quality protocol document is essential for the successful and efficient implementation of clinical trials, but there is no consensus on how clinical trial protocol document quality should be evaluated. We used a modified Delphi approach and cognitive interviews to develop a new protocol document quality assessment tool, the <i>Protocol Quality Rating Tool (PQRT)</i>. We compiled a checklist of elements that should be included in a high-quality trial protocol document and asked experts to rate the importance of each element. We developed the <i>PQRT</i> by describing the expected content of each element and identified essential vs. additional (bonus) content to differentiate high- versus low-quality protocol documents and then organized the elements into 18 sections. We revised the <i>PQRT</i> based on feedback from and cognitive interviews with our protocol quality rating team. We then tested the <i>PQRT</i> using ten protocol documents previously approved by the Institutional Review Board. All the protocol quality raters found the tool easy to use and their scores were highly concordant for eight of ten protocol documents. We have developed and tested a simple tool to measure clinical trial protocol document quality and encourage other researchers to evaluate and validate it.</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.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879951","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":"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}