British journal of clinical pharmacology最新文献

{"title":"First-in-human, phase I, randomized, safety, pharmacokinetic, food-effect and pharmacodynamic study of a tyrosine kinase 2/Janus kinase 1 inhibitor, SDC-1801.","authors":"Chris Brearley, Sam Francis, John Reader, Judi Proctor","doi":"10.1002/bcp.70642","DOIUrl":"10.1002/bcp.70642","url":null,"abstract":"<p><strong>Aim: </strong>The purpose of this study is to evaluate safety, tolerability, pharmacokinetics (PK), food-effect (FE) and pharmacodynamics (PD) of an oral tyrosine kinase-2 (TYK2)/Janus kinase-1 (JAK1) inhibitor, SDC-1801, in healthy adult participants.</p><p><strong>Methods: </strong>This first-in-human study randomized 95 male and female participants. Parts one and two were double-blind, placebo-controlled escalation designs, investigating single (5, 10, 30, 75, 150 mg) and multiple (30, 100, 75, 140 mg/day) doses of SDC-1801 or matching placebo. Part three evaluated the FE of 75 mg SDC-1801 in an open-label, crossover design.</p><p><strong>Results: </strong>There were no deaths or treatment-related serious adverse events (AEs) following SDC-1801, up to 150 mg; no treatment-emergent AEs (TEAEs) were severe with non-related headache most frequently reported. PK showed low to moderate variability and no consistent dose-exposure relationship; T_max occurred 3-5 h post-dose with a geometric mean (GM) t_1/2 of 15.2-27.0 h. Bioavailability appeared solubility limited, with lower exposure from the higher strength capsule and modestly higher exposure in the fed state. No safety stopping criteria were met. PD assessments demonstrated anti-inflammatory activity, with IFN-gamma induced protein-10 (IP-10), high sensitivity C reactive protein (hsCRP), and signal transducer and activator of transcription (STAT3/5) phosphorylation reductions with increasing exposure giving greater inhibition. At the highest exposure, there was a clear reduction of IP-10 levels at pre-dose on day 9, which rebounded following drug withdrawal.</p><p><strong>Conclusions: </strong>SDC-1801 was well tolerated to 150 mg; all TEAEs were mild or moderate, with unrelated headache most frequently reported. The PK profile supports the potential for a once- or twice-daily regimen, with evidence of target engagement for both TYK2 and JAK1.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3513-3526"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293405","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":"Comparative effectiveness of dapagliflozin vs. empagliflozin on major adverse cardiovascular events in patients with heart failure with reduced ejection fraction: A real-world prospective cohort study.","authors":"Tuong Le Trong Huynh, Hien Dieu Tran, Phong Thanh Pham, Nhan Dinh Tran, Nhan Thanh Nguyen, Huyen Doan Thi Bich Cao, Son Ngoc Nguyen, Anh Phuoc Lan Nguyen, Thoai Anh Nguyen, Sang Phu Bui, Trung Quang Le, Toan Hoang Ngo, Son Kim Tran","doi":"10.1002/bcp.70654","DOIUrl":"10.1002/bcp.70654","url":null,"abstract":"<p><strong>Background: </strong>Dapagliflozin and empagliflozin are sodium-glucose cotransporter-2 inhibitors (SGLT2i) with equivalent Class IA guideline recommendations in heart failure with reduced ejection fraction (HFrEF).</p><p><strong>Objectives: </strong>To compare the incidence of major adverse cardiovascular events (MACE) between dapagliflozin and empagliflozin in HFrEF patients treated in routine clinical practice.</p><p><strong>Methods: </strong>This prospective real-world cohort study enrolled 1231 consecutive HFrEF patients (left ventricular ejection fraction ≤40%) at Can Tho Central General Hospital, Vietnam (March 2023 to March 2026). Patients received dapagliflozin (n = 622) or empagliflozin (n = 609) as part of optimized guideline-directed medical therapy and the primary outcome was MACE.</p><p><strong>Results: </strong>MACE occurred in 64 patients (10.3%) receiving dapagliflozin and 111 patients (18.2%) receiving empagliflozin. Following propensity score matching and multivariable adjustment, dapagliflozin was associated with significantly lower odds of MACE (adjusted odds ratio [OR] 0.46; 95% confidence interval [CI] [0.30, 0.67]; p < 0.001). Hospitalization for heart failure was significantly lower with dapagliflozin (8.7% vs. 14.9%; adjusted OR 0.52; 95% CI [0.33, 0.80]; p = 0.003). Corrected all-cause mortality was 13/622 (2.1%) with dapagliflozin and 25/609 (4.1%) with empagliflozin (p = 0.048). Multivariable logistic regression identified four independent predictors of MACE: New York Heart Association functional class III-IV (adjusted OR 15.54; 95% CI [9.09, 28.99]; p < 0.001), sedentary lifestyle (adjusted OR 2.11; 95% CI [1.42, 3.37]; p < 0.001), premature cardiovascular disease history (adjusted OR 2.30; 95% CI [1.29, 4.43]; p = 0.007) and dapagliflozin as an independent protective factor (adjusted OR 0.47; 95% CI [0.31, 0.68]; p < 0.001).</p><p><strong>Conclusions: </strong>In this real-world prospective Vietnamese HFrEF cohort followed over 36 months, dapagliflozin was associated with significantly lower odds of MACE and HF hospitalization compared with empagliflozin, with robust adjustment for confounding.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3546-3558"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACEi/ARB in adults older than 85 years after AKI: Beyond single-drug paradigm to phenotype-guided care.","authors":"Wenbo Hu, Menglu Ni, Jian Kang","doi":"10.1002/bcp.70679","DOIUrl":"10.1002/bcp.70679","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3691-3693"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of cumulative glucocorticoid exposure on vancomycin clearance in hospitalized children: A retrospective cohort study.","authors":"Kouki Tomari, Ruud H J Verstegen, Cintia Cruz, Erin Chung, Aleena Azim, Shinya Ito, Tamorah R Lewis","doi":"10.1002/bcp.70672","DOIUrl":"10.1002/bcp.70672","url":null,"abstract":"<p><strong>Introduction: </strong>Augmented renal clearance (ARC) can lead to subtherapeutic vancomycin exposure in children. The impact of prior glucocorticoid (GC) exposure on vancomycin pharmacokinetics remains poorly understood. We evaluated the association between GC exposure and vancomycin clearance in paediatric patients.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study of paediatric patients undergoing vancomycin therapeutic drug monitoring. GC exposure within 2 years was quantified as prednisolone-equivalent dose. Vancomycin clearance was estimated using the allometrically normalized dose-to-level (D/L) ratio. Associations were assessed using correlation and multivariable regression adjusted for age, sex, eGFR and inflammatory markers.</p><p><strong>Results: </strong>Among 245 hospitalized children receiving vancomycin, 157 (64.1%) had prior GC exposure. GC-exposed children had higher vancomycin D/L ratios (p = .018). Cumulative GC exposure showed weak positive associations with higher vancomycin clearance (2-year window: Spearman ρ = .16, p = .013). However, in the fully adjusted model, the association between cumulative GC exposure and D/L ratio was not significant (β = -.0077 per 10 mg kg^-1, 95% CI -0.026 to 0.010, p = .40). GC exposure was associated with higher odds of subtherapeutic trough concentrations (<10 mg/L) (odds ratio 1.45, 95% CI 1.04-2.01).</p><p><strong>Conclusions: </strong>Children with prior GC exposure had lower early vancomycin trough concentrations and higher unadjusted D/L ratios. However, the association between GC exposure and vancomycin clearance was attenuated after adjustment, suggesting that GC exposure may reflect underlying physiologic or disease-related factors rather than an independent determinant of clearance. Closer therapeutic drug monitoring may be warranted at treatment initiation.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3598-3610"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367115","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":"Comparative bioavailability of sublingual vs. oral levothyroxine in patients with post-thyroidectomy hypothyroidism: A single-dose pilot study.","authors":"Osama Shoaip, Mahmoud Bassiony, Rana Elbayar, Mohanned Mohsen, Hagar Elhammady, Rawda Elsaadany, Nehal M Ramadan","doi":"10.1002/bcp.70661","DOIUrl":"10.1002/bcp.70661","url":null,"abstract":"<p><strong>Aim: </strong>To evaluate the relative bioavailability of sublingual vs. oral levothyroxine (L-T4) in post-thyroidectomy patients, aiming to overcome gastrointestinal absorption variability.</p><p><strong>Methods: </strong>This open-label, randomized, parallel-group pilot study enrolled 15 de novo hypothyroid patients following total thyroidectomy (oral: n = 7, sublingual: n = 8). Participants received a single 700-μg L-T4 dose under fasting conditions. Pharmacokinetic parameters, including baseline-corrected AUC, Cmax and Tmax, were determined via noncompartmental analysis.</p><p><strong>Results: </strong>Sublingual administration resulted in a Geometric Mean Ratio (GMR) of 1.283 (90% CI: 0.849-1.938) for total systemic exposure (AUC_0-∞) and 1.123 (90% CI: 0.815-1.547) for early exposure (AUC_0-48) compared to the oral route. Due to the small sample size and inter-subject variability, these differences did not reach statistical significance. Elimination kinetics (T_1/2, MRT) were route-independent, while sublingual delivery showed lower apparent clearance (CL/F), supporting improved bioavailability.</p><p><strong>Conclusion: </strong>Sublingual L-T4 achieved numerically higher systemic exposure with comparable elimination kinetics to the oral route. These findings suggest sublingual delivery is a promising, practical alternative that mitigates fasting constraints. Large-scale crossover studies are needed to definitively establish bioequivalence and long-term efficacy.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3527-3533"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative risk of ventricular arrhythmia and sudden cardiac death among acetylcholinesterase inhibitors in dementia: A population-based cohort study.","authors":"Hsi-Yu Lai, Lin-Chieh Meng, Yi-Jia Ye, Ho-Min Chen, Liang-Kung Chen, Fei-Yuan Hsiao","doi":"10.1002/bcp.70656","DOIUrl":"10.1002/bcp.70656","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have suggested that acetylcholinesterase inhibitors (AChEIs) may be associated with an increased risk of ventricular arrhythmia or sudden cardiac death, potentially related to QTc prolongation. However, evidence comparing the real-world risk of severe cardiac conduction outcomes among the three AChEIs-donepezil, galantamine and rivastigmine-remains limited.</p><p><strong>Objective: </strong>This study aimed to compare the risk of ventricular arrhythmia or sudden cardiac death associated with the use of different AChEIs in older adults with dementia.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study using Taiwan's National Health Insurance database. Older adults diagnosed with dementia who initiated AChEI therapy between 2010 and 2019 were identified and categorized according to the AChEI prescribed. Participants were followed until the end of 2020. Stabilized inverse probability of treatment weighting was applied to balance baseline characteristics, with rivastigmine serving as the reference group. Cox proportional hazards models were used to estimate hazard ratios for ventricular arrhythmia or sudden cardiac death.</p><p><strong>Results: </strong>A total of 66 589 older adults with dementia initiating AChEI therapy were included. Donepezil was the most frequently prescribed AChEI (64.8%), followed by rivastigmine (33.0%) and galantamine (2.3%). Compared with rivastigmine, IPTW-weighted analyses showed no significant association between donepezil use (HR 0.95, 95% CI, 0.82-1.09) or galantamine use (HR 1.40, 95% CI, 0.90-2.18) and the risk of ventricular arrhythmia or sudden cardiac death.</p><p><strong>Conclusions: </strong>The risk of ventricular arrhythmia or sudden cardiac death was comparable among donepezil, galantamine and rivastigmine in older patients with dementia.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3634-3645"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on 'Sequential nephron blockade vs. sequential renin-angiotensin system blockade on central and ambulatory blood pressure in resistant hypertension: A randomized clinical trial'.","authors":"Mohammad Rafi Shaik, Ashwin Kamath","doi":"10.1002/bcp.70704","DOIUrl":"10.1002/bcp.70704","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3698-3699"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From under-reporting to over-capture: Prioritizing preventable harm in ICD-10 ADR surveillance.","authors":"Jinian Chen","doi":"10.1002/bcp.70698","DOIUrl":"10.1002/bcp.70698","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3696-3697"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained pharmacodynamic effects of S-ketamine on cortical excitability and resting-state brain activity: A randomized, placebo-controlled trial.","authors":"Catherine M K E de Cuba, Annika A de Goede, Joost C van Mechelen, Laura G J M Borghans, Liam van der Aa, Erik Olofsen, Maria J Juachon, Robert J Doll, Amy Gillespie, Catherine J Harmer, Gabriël E Jacobs, Jules A A C Heuberger","doi":"10.1002/bcp.70649","DOIUrl":"10.1002/bcp.70649","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to investigate a set of pharmacodynamic biomarkers reflecting acute, delayed and sustained central nervous system effects of S-ketamine, used as a tool compound for rapid-acting antidepressant activity, with the goal of informing biomarker strategies for delayed antidepressant effects.</p><p><strong>Methods: </strong>In this randomized, double-blind, double-dummy, placebo-controlled, 4-way crossover study in 16 healthy participants, we administered S-ketamine in a therapeutic intravenous dose (IV), a low and high oral dose, versus placebo. Measurements were conducted from baseline up to 7 days post-dose using Transcranial Magnetic Stimulation combined with electromyography (TMS-EMG) and encephalography (TMS-EEG), pharmaco-electroencephalography (pEEG), alongside drug and metabolite plasma concentrations. Outcomes were analysed using mixed-effects ANCOVA and cluster-based permutation testing. Post-hoc concentration-effect relationships were explored.</p><p><strong>Results: </strong>IV S-ketamine induced an acute reduction in motor-evoked potential (MEP) amplitude and sustained attenuation of long-interval intracortical inhibition (LICI₅₀), the latter showing a linear concentration-effect relationship with the parent compound. Acute TEP modulation was observed across all treatments, whereas delayed effects occurred only after IV and high-dose oral. pEEG showed acute reductions in alpha, beta and delta power (eyes closed) and sustained increases in delta power (eyes open) following IV and high-dose oral S-ketamine; with delta power exhibiting a less analyte-specific linear concentration-effect relationship.</p><p><strong>Conclusion: </strong>We provide evidence suggestive of delayed pharmacodynamic effects of S-ketamine in healthy participants sustained up to 7 days post-dose, using TMS and pEEG derived measures, which are markedly distinct from its acute effects and may be relevant to understand its antidepressant efficacy.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3534-3545"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307260","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 and pharmacodynamics of canagliflozin in paediatric patients with type 2 diabetes mellitus.","authors":"Nele Goeyvaerts, Per Olsson Gisleskog, Martine Neyens, Juan José Perez Ruixo, Saberi Rana Ali, Iolanda Cirillo, Oliver Ackaert","doi":"10.1002/bcp.70644","DOIUrl":"10.1002/bcp.70644","url":null,"abstract":"<p><strong>Aims: </strong>Canagliflozin was recently approved in type 2 diabetes mellitus (T2DM) patients ≥10 and <18 years old as a single agent dosed once daily (QD) or in a fixed-dose combination with metformin dosed twice daily (BID). We characterize canagliflozin pharmacokinetics in paediatric patients with T2DM, compare estimated individual and simulated exposure metrics for QD and BID doses in paediatric patients and adults, and investigate the relationship between canagliflozin plasma concentrations and change from baseline HbA1c with QD and BID doses.</p><p><strong>Methods: </strong>Paediatric population pharmacokinetics and pharmacokinetics/pharmacodynamics models were based on the previously developed corresponding adult models, using Phase 1 and 3 study data, evaluating canagliflozin 100- or 300-mg QD doses in paediatric patients with T2DM. Modelling encompassed exploratory analysis, external evaluation, model update and simulation of canagliflozin exposure metrics and HbA1c for QD and BID doses.</p><p><strong>Results: </strong>Estimated and simulated steady-state area under the concentration-time curve during 24 h (AUC_24h) and maximum drug concentration were comparable between paediatric patients and adults for canagliflozin 100- or 300-mg QD. Simulated steady-state AUC_24h was similar between QD and BID dosing for the same canagliflozin total daily dose in paediatric patients and adults with T2DM. QD to BID bridging was supported by simulated HbA1c and change from baseline in HbA1c in paediatric patients.</p><p><strong>Conclusions: </strong>No canagliflozin dose adjustments are required alone or in combination with metformin to ensure similar plasma exposures between paediatric and adult patients with T2DM, as well as similar HbA1c lowering between QD and BID dosing in paediatric patients.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3622-3633"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367095","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}