Clinical Pharmacology & Therapeutics最新文献

{"title":"Effects of Trimethoprim on Three Previously Proposed Putative Biomarkers for OCT2/MATE-Mediated Renal Drug-Drug Interactions in Healthy Volunteers.","authors":"Jana Picurová, Fabian Müller, Daniel Auge, Jörg König, Martin F Fromm, Arne Gessner","doi":"10.1002/cpt.70384","DOIUrl":"10.1002/cpt.70384","url":null,"abstract":"<p><p>Regulatory agencies request the assessment of the potential of new drugs to cause transporter-mediated drug-drug interactions (DDI). This assessment can be improved by integrating endogenous biomarkers during drug development. Regarding the renal excretion of drugs such as metformin, the organic cation transporter (OCT) 2 and multidrug and toxin extrusion proteins (MATE) 1 and 2-K are of major importance. However, fully validated, sensitive, and specific biomarkers for these transporters are still lacking. In previous in vivo and in vitro studies, 5-aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1-methylhistamine (1MH) emerged as promising biomarker candidates for OCT2/MATE-mediated DDI. Therefore, we further investigated their suitability for clinical risk assessment by evaluating the effects of the OCT2/MATE inhibitor trimethoprim in healthy volunteers and by determining IC₅₀ values for the inhibition of OCT2- and/or MATE1-mediated uptake of the potential biomarkers by trimethoprim, cimetidine, pyrimethamine, and dolutegravir in vitro. Trimethoprim reduced the amount excreted into urine of 5AVAB, 5HT, and 1MH in vivo by 95.1 ± 5.67%, 78.9 ± 6.56%, and 51.9 ± 14.3%, respectively (all P < 0.001) as well as the renal clearance of 5AVAB and 5HT by 93.6 ± 5.85% and 73.8 ± 12.8%, respectively (both P < 0.001). When comparing the IC₅₀ values with unbound inhibitor plasma concentrations, trimethoprim, cimetidine, and pyrimethamine preferentially inhibit the MATE1-mediated transport, whereas dolutegravir inhibits the OCT2-mediated transport of the biomarker candidates. In conclusion, this study further supports the suitability of 5-aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1-methylhistamine (1MH) as promising biomarkers for OCT2/MATE-mediated DDI.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1016-1026"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Hy's Law: Importance of Markedly Elevated Aminotransferases without Hyperbilirubinemia.","authors":"Naga Chalasani, Ismael Alvarez-Alvarez, Paul H Hayashi, Raj Vuppalanchi, Marwan Ghabril, Ronald Kamusiime, Huiman Barnhart, Hao Niu, M Isabel Lucena, Raul J Andrade","doi":"10.1002/cpt.70397","DOIUrl":"10.1002/cpt.70397","url":null,"abstract":"<p><p>Elevated aminotransferases with concomitant jaundice in drug-induced liver injury (DILI) are associated with adverse outcomes, but the prognostic significance of very high aminotransferases without jaundice is unclear. We examined selected outcomes of patients with DILI and markedly elevated aminotransferases but normal or near-normal total bilirubin (TBL). We analyzed the data from the prospective Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI registries. Patients were categorized based on peak alanine or aspartate aminotransferase (ALT/AST) levels-very high (500-1,000 U/L) or towering (>1,000 U/L)-and concomitant normal (≤1.0 mg/dL) or near-normal (1.1-2.5 mg/dL) TBL levels. Primary outcome was subsequent development of nR-based Hy's Law (nR ≥5 with TBL >2.5 mg/dL). A total of 964 patients were analyzed (692 DILIN; 272 Spanish DILI). In both cohorts, very high aminotransferases with normal TBL were rarely followed by nR-based Hy's Law. In DILIN, only 1.3% of patients with very high ALT and normal TBL developed nR-based Hy's Law, whereas risk increased markedly with minimally elevated TBL (odds ratio (OR) 7.8). Towering aminotransferases conferred increased risk regardless of TBL, with the highest risk observed when accompanied by minimally elevated TBL (OR 23.6). Similar inflection points were observed in the Spanish DILI Registry, in patients with very high aminotransferases and minimally elevated TBL or towering aminotransferases with or without elevated TBL. In conclusion, patients with DILI and very high aminotransferases may tolerate liver injury well when bilirubin is normal, but even minimal bilirubin elevation or towering aminotransferases signal increased risk for poor outcomes.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1041-1048"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular Safety of Febuxostat vs. Allopurinol in Gout Patients with Cardiovascular Diseases: A Target Trial Emulation.","authors":"Xiuwen Wang, Xu Cheng, Yixuan Wang Wan, Yu Wang, Shuaijie Ding, Zhenhua Ying","doi":"10.1002/cpt.70403","DOIUrl":"10.1002/cpt.70403","url":null,"abstract":"<p><p>Guidelines recommend febuxostat and allopurinol as first-line urate-lowering therapies (ULTs) for gout, yet the cardiovascular safety of febuxostat remains debated, with conflicting randomized trials (CARES, FAST) results and limited real-world evidence in high-risk patients. This target trial emulation study evaluated the long-term cardiovascular safety of febuxostat vs. allopurinol in gout patients with preexisting cardiovascular disease (CVD) using US collaborative electronic health records. We included 7555 propensity-score matched (42 covariates) pairs of adults aged ≥ 50 years initiating either febuxostat or allopurinol. The primary outcome of our study was the occurrence of major adverse cardiovascular events (MACE) and the secondary outcome was all-cause mortality. During a 10-year follow-up period (median 1,558 days), MACE risk was comparable (HR: 1.027; 95% CI: 0.978-1.079) between the two groups. Febuxostat was associated with modestly increased all-cause mortality (HR: 1.125; 95% CI: 1.039-1.217). Risk elevations were consistent across subgroups (White race, males, nonsmokers, etc.). Sensitivity analyses confirmed robustness. Findings suggest cautious febuxostat use in CVD patients, guiding personalized prescribing based on racial and lifestyle factors.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1057-1067"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13426092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148628939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antipsychotic Drug Interactions and Short-Term Mortality Risk in People With Dementia: A National Cohort Study.","authors":"Edward C Y Lau, Grace H Shim, Chin Hang Yiu, Sarah N Hilmer, Yun-Hee Jeon, Weisi Chen, Christine Y Lu, Edwin C K Tan","doi":"10.1002/cpt.70407","DOIUrl":"10.1002/cpt.70407","url":null,"abstract":"<p><p>Antipsychotics are often prescribed in the management of behaviors and psychological symptoms of dementia. While the potential harms of antipsychotic use in people with dementia have been established, little is known about the risk associated with antipsychotic drug-drug interactions (DDIs). This study aims to examine the patterns of antipsychotic DDIs and their association with 90-day mortality among people with dementia using antipsychotics. This retrospective cohort study utilized Australian nationwide linked 2021 Census and Pharmaceutical Benefits Scheme data. People with dementia aged ≥ 65 years who initiated a single antipsychotic (risperidone, quetiapine, aripiprazole, haloperidol, or olanzapine) between August 2021 and July 2022 were included. Antipsychotic DDIs were defined by Micromedex® Drug-Reax, and were stratified by number, severity, and pharmacological mechanism. Mortality risk was assessed using modified Poisson regression and confounding was addressed with overlapped weighting. Among 9064 incident antipsychotic users, 6913 (76.3%) were exposed to ≥ 1 DDI, with the majority of them classed as \"major\" severity (n = 6709). Nervous system drugs were the most commonly interacting agents. When compared to those without antipsychotic interactions, those with ≥ 1 DDI had a 43% increased risk of 90-day mortality (adjusted relative risk [aRR]: 1.43; 95% confidence interval [CI]: 1.22-1.69), while those with ≥ 2 DDIs had an 80% increased risk (aRR: 1.80; 95% CI: 1.49-2.17). Overall, antipsychotic DDIs are common among older adults with dementia and are associated with increased risk of 90-day mortality. As such, medication review and regular monitoring is important when initiating antipsychotics in this vulnerable population.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1081-1091"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13409323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148596984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Money, Meals, and Marketing in Medicine: A 13-Year Follow-Up Survey of Physicians.","authors":"Helen Mooney, Kirsten Austad, Eric G Campbell, Jerry Avorn, Zhigang Lu, Aaron S Kesselheim","doi":"10.1002/cpt.70425","DOIUrl":"10.1002/cpt.70425","url":null,"abstract":"<p><p>Pharmaceutical company marketing to physicians is known to impact prescribing patterns. In 2011, we surveyed medical students and residents about physician/industry relationships. In 2024, we resurveyed the same participants to study changes in their behaviors over time and their current opinions of policies regulating interactions between physicians and industry. In both surveys, respondents were asked to report whether they had received gifts or financial support from industry or interacted with pharmaceutical representatives. We also asked which resources they used to learn about drugs. In 2024, we added questions to evaluate conflict of interest policies in patient care institutions. We performed chi-squared tests on reported behaviors in 2011 and 2024. For 2024 questions about policies governing interactions, chi-squared tests evaluated the association between responses and participants' reported receipt of gifts from the pharmaceutical industry. Of the 294 respondents (33% response rate), 283 participants remained available for analysis after meeting our exclusion criteria. Participants were generally consistent in the magnitude and types of gifts they reported in 2011 and 2024. By contrast, there were important changes in their use of resources to learn about drugs. About one in four physicians did not know whether their institutions had policies governing interactions with the pharmaceutical industry, though respondents expressed support for meaningful limits on such relationships.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1142-1148"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13453129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148696755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adverse Reactions Identified after Approval of Novel Medicines: Analysis of 339 New Molecular Entities and Therapeutic Biologics.","authors":"Ellen Pinnow, Brendan Day, Esther H Zhou, Corinne Woods, Nana Dwumfour, Jenni Y Lee, Ilynn Bulatao, Sanae Cherkaoui, Manish Kalaria, Sonja Brajovic, Nabila Sadiq, Farideh Sistani, Maggie Lee, Grace Chai, Gerald Dal Pan","doi":"10.1002/cpt.70422","DOIUrl":"10.1002/cpt.70422","url":null,"abstract":"<p><p>Postmarketing safety surveillance data identify safety issues not identified in preapproval clinical trials. We describe the frequency of new safety issues overall and by labeling section and the relationship of the most commonly added safety issues with the cumulative number of prescriptions dispensed via retail pharmacies. Using publicly available sources, we determined the frequency of the most common safety issues added after approval overall and by labeling section (Boxed Warning, Warnings and Precautions, and Adverse Reactions) for new molecular entities (NMEs) and new therapeutic biologics (NTBs) approved between 10/1/2002 and 12/31/2014. There were 339 products in the cohort (278 NMEs and 61 NTBs) with a median follow up of 13.1 years. There were 5,161 new safety issues overall. The most frequently added to the product labeling were anaphylactic reaction, angioedema, Stevens-Johnson syndrome (SJS), hypersensitivity, and toxic epidermal necrolysis (TEN), which were added to the labeling of at least 12% of the 339 products. This was similar between NMEs and NTBs, except for cardiac failure, which was among the five most frequent adverse reactions (AR) added to NTBs, while TEN was less frequently added. Most other ARs were added to 10% or fewer products. Among drugs used primarily in the outpatient setting, the mean number of cumulative dispensed prescriptions exceeded 1 million at the time a safety issue was added to the labeling. Many of the most frequently added ARs are drug hypersensitivities. These findings are relevant to practitioners and patients, who should be alerted to the possibility of such reactions.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1120-1128"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Immune Response after Oral Cholera Vaccination (OCV) and Effects of Mycophenolate Mofetil on Priming of this Immune Response-A Randomized, Placebo-Controlled Trial.","authors":"Boukje C Eveleens Maarse, Aliede E In 't Veld, Hendrika W Grievink, Manon A A Jansen, Matthijs Moerland","doi":"10.1002/cpt.70399","DOIUrl":"10.1002/cpt.70399","url":null,"abstract":"<p><p>Mycophenolate mofetil (MMF) is an immunosuppressive drug widely used by solid organ transplant recipients. Although it is known that MMF suppresses immune responses, its exact effects on specific vaccinations have not been investigated yet. Mucosal vaccinations are increasingly used, such as a cholera vaccination consisting of two oral immunizations (oral cholera vaccination; OCV). This study aimed to investigate the specific immunosuppressive effects of MMF use during the first dose of OCV in a randomized, placebo-controlled trial in healthy volunteers. Moreover, the study aimed to characterize the immune response provoked by OCV in detail. This randomized, placebo-controlled, single-blind trial included 16 healthy volunteers, each receiving two doses of Dukoral® and an intranasal rechallenge. Outcome measures were serum antibody responses (IgA and IgG) and IgA levels in saliva. Additionally, peripheral blood mononuclear cells (PBMCs) of participants were investigated for ex vivo cytokine production and expression of tissue-specific homing markers after OCV. There were considerable serum IgA and IgG responses after vaccination. MMF-treated volunteers still showed a significant cholera antibody response, though data suggest a potential suppression by MMF without reaching statistical significance. There was no substantial IgA response in saliva. Investigation of PBMCs from OCV-treated participants showed a Th2 skewing with increased ex vivo production of TNF, IL-2, IL-5, IL-13, and IL-22 compared to the placebo group. Taken together, this study provides a framework for future clinical pharmacology studies building on OCV as a challenge model and for further investigation of specific effects of MMF on mucosal vaccination responses.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1049-1056"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13388473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disentangling Sex Differences in Sulfonylurea Drug Response With Genome-Wide Association Studies in Individuals With Type 2 Diabetes.","authors":"Joseph H Breeyear, John S House, Mark Kvale, Stella Nam, Farida S Akhtari, Hetal S Shah, Monique M Hedderson, Kathleen M Giacomini, Josyf C Mychaleckyj, Alessandro Doria, Michael J Wagner, Josephine H Li, Sook Wah Yee, John B Buse, Richard P Woychik, Daniel M Rotroff, Alison A Motsinger-Reif","doi":"10.1002/cpt.70381","DOIUrl":"10.1002/cpt.70381","url":null,"abstract":"<p><p>Sulfonylureas are a cornerstone of type 2 diabetes therapy despite interindividual variability in response. Despite well-documented sex-based differences, pharmacogenomic and genome-wide association studies (GWAS) have largely overlooked sex as a biological variable. We conducted the first sex-stratified GWAS of hemoglobin A1c (HbA1c) response to sulfonylureas in Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial participants (N = 871). Variants meeting genome-wide (P < 5.0 × 10^-8) and suggestive (P < 5.0 × 10^-6) significance were assessed for replication in the Pharmacogenomics of Metformin (PMET1) cohort. Replicated variants were further analyzed in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) cohort to assess acute insulin and glucose responses to a single glipizide dose. Genome-wide significant loci with sex-specific effects were identified: KAZN, KIF2B, SLC39A10, and SPINK5 (combined-sex); CRACR2A, KCNK2, and TENM2 (male-only); and NACPH2 (female-only). Two suggestive variants in the TMEM64/NECAB1 locus, associated with reduced HbA1c response to sulfonylureas in the male-only ACCORD analysis, were directly replicated in the PMET1 male-only cohort. In SUGAR-MGH, one replicated variant (rs6471250-C) was significantly associated with reduced peak insulin in males (P = 0.035) but not females (P = 0.40), demonstrating sex-specific functional effects. This study identified statistically supported and biologically plausible loci with prior evidence linking nearby genes to pathways relevant to sulfonylurea action, including insulin secretion, insulin regulation/sensitivity, calcium signaling, potassium-channel biology, and glucose transport. The findings highlight sex-specific differences in sulfonylurea response, providing mechanistic insights and underscoring the importance of sex-specific precision medicine. Identification of genetic variants influencing sex-specific response could inform dosing to optimize sulfonylureas.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1004-1015"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Function Assignment of NAT2 Alleles by the Clinical Pharmacogenetics Implementation Consortium Pharmacogene Curation Expert Panel.","authors":"Bailey M Tibben, David W Hein, Michelle Whirl-Carrillo, Andrea Gaedigk, Michael T Eadon, Rodney F Minchin, Sotiria Boukouvala, Adalberto Rezende Santos, Roseann S Donnelly, José A G Agúndez, Kelly E Caudle","doi":"10.1002/cpt.70420","DOIUrl":"10.1002/cpt.70420","url":null,"abstract":"<p><p>NAT2 encodes arylamine N-acetyltransferase 2, a key enzyme in the phase II metabolism of arylamines and arylhydrazines. NAT2 is highly polymorphic, resulting in variable distributions of rapid and poor metabolizers across global populations. Here, we detail the process undertaken by the Clinical Pharmacogenetics Implementation Consortium (CPIC) NAT2 Pharmacogene Curation Expert Panel (PCEP) to assign clinical function to NAT2 star (*) alleles using CPIC's standard terminology. Given the observed impact of NAT2 genetic variability on drug response, CPIC convened the NAT2-PCEP to standardize clinical allele function assignments. The NAT2-PCEP is comprised of multidisciplinary and international members, including researchers, clinicians, and implementers with expertise in pharmacogenomics and NAT2 molecular biology. Extensive in vitro and clinical literature was curated from PubMed and other sources to assess NAT2 genotype-to-phenotype concordance as well as the biochemical function of NAT2 star alleles. The NAT2-PCEP assigned allele clinical function using CPIC's standard terminology (increased, decreased, uncertain, and unknown function) to 59 star alleles cataloged by the Pharmacogene Variation Consortium (PharmVar). Two alleles, NAT2*1 and NAT2*4, were assigned increased function (historically known as rapid), 40 alleles were assigned decreased function (historically known as slow), 10 alleles were assigned uncertain function, and seven alleles were assigned unknown function. Rigorous evidence review and in-depth PCEP discussion were crucial in determining these function assignments. The findings reported here underscore the importance of standardized allele functional terms and diplotype-to-phenotype assignments to further the clinical implementation of NAT2 pharmacogenetic test results.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1101-1110"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13427928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early and High-Dose Glucocorticoid Use and Survival in Advanced NSCLC Receiving Immune Checkpoint Inhibitors: A Multicenter Target Trial Emulation.","authors":"Da Eun Lee, Geunho Lim, Minoh Ko, Mari Kim, Ji Sun Chun, Borim Lee, Miso Kim, Kwangsoo Kim, Byung Kwan Choi, Jeongmin Seo, Jin Hyoung Kang, Taehoon Ko, In-Wha Kim, Jung Mi Oh","doi":"10.1002/cpt.70424","DOIUrl":"10.1002/cpt.70424","url":null,"abstract":"<p><p>Despite the immunomodulatory mechanism of immune checkpoint inhibitors (ICIs), systemic glucocorticoids are commonly used in advanced non-small cell lung cancer (NSCLC). Evidence regarding their effects on ICI outcomes is inconsistent, in part due to confounding by indication and immortal time bias. We conducted a multicenter target trial emulation to assess the association of glucocorticoid timing and dose with survival outcomes while addressing these biases. Patients with advanced NSCLC who initiated ICI therapy between 2015 and 2021 at four Korean tertiary hospitals were included. The primary endpoint was 2-year overall survival (OS), with disease progression as a secondary endpoint. To minimize biases, outcomes were compared between concomitant glucocorticoid users and non-users using time-dependent propensity score matching. Among 1,815 eligible patients, 1,128 were matched. Hazard ratios (HRs) from the four institutions were pooled using a random-effects meta-analysis. Concomitant glucocorticoid use was associated with an increased risk of mortality (pooled aHR 1.36; 95% CI, 1.06-1.75). Early exposure within 90 days of ICI initiation was associated with poorer OS (aHR 1.49; 95% CI, 1.18-1.87), whereas later initiation showed no association. Dose-stratified analyses showed that high-dose exposure (> 1 mg/kg/day) was associated with reduced survival (aHR 1.61; 95% CI, 1.31-1.99), whereas low-dose exposure was not associated with adverse outcomes. After accounting for confounding by indication and time-related biases, concomitant systemic glucocorticoid use during ICI therapy was associated with less favorable survival outcomes. This association was more pronounced with early and high-dose exposure, underscoring the clinical importance of glucocorticoid timing and dose.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":"1129-1141"},"PeriodicalIF":4.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13438008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}