British journal of clinical pharmacology最新文献

{"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":"Cardiovascular and neuroendocrine dynamics in antibiotic dose individualization in intensive care.","authors":"Mehmet Ertugrul Balkar","doi":"10.1002/bcp.70688","DOIUrl":"10.1002/bcp.70688","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3694-3695"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403533","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}

{"title":"Predicting cognitive function in Alzheimer's clinical trials via amyloid β-protein biomarkers.","authors":"Zichao Sui, Aobo Feng, Yiwen Gong, Sijie Zha, Yinghua Lv, Qingshan Zheng, Lujin Li, Yaning Wang","doi":"10.1002/bcp.70665","DOIUrl":"10.1002/bcp.70665","url":null,"abstract":"<p><strong>Objectives: </strong>This study investigates the association between amyloid-β (Aβ) biomarkers and clinical cognitive outcomes and quantitatively elucidates their relationship, providing robust evidence supporting the amyloid hypothesis and advancing the development of novel anti-amyloid therapeutics, such as aducanumab, lecanemab and donanemab.</p><p><strong>Methods: </strong>Placebo-controlled randomized clinical trials reporting Aβ-related biomarkers and cognitive function clinical outcomes were retrieved from PubMed, EMBASE and Cochrane Library. Pearson correlation analysis was first used to screen indices, and then a model-based meta-analysis (MBMA) using non-linear mixed-effect modelling was established to predict cognitive function based on biomarkers while examining relevant factors affecting the relationship.</p><p><strong>Results: </strong>Primary outcomes included changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-COG-11). The analysis included 57 articles representing 93 417 subjects, with a modelling subset of 18 246 patients providing paired biomarker-endpoint data for Alzheimer's disease or mild cognitive impairment. Results showed significant correlations between the standard uptake value ratio (SUVR) of β-amyloid plaques and CDR-SB, centiloid and CDR-SB, and SUVR and ADAS-COG-11. Three prediction models of cognitive function scales based on imaging index of β-amyloid plaques were established and found to be significantly impacted by factors such as baseline CDR-SB, treatment duration and the proportion of patients receiving basic treatment.</p><p><strong>Conclusions: </strong>This study clarified the correlation and established predictive models for CDR-SB and ADAS-COG-11 based on amyloid imaging. This research identifies potential biomarkers and model-derived benchmarks for future dose selection and decision-making in Alzheimer's drug development, potentially accelerating the development of new treatments.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3576-3585"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343885","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":"The effect of mild and moderate hepatic impairment on the pharmacokinetics, safety and tolerability of balcinrenone.","authors":"Anna L Eriksson, Deeyen Karsanji, Bonifride Tuyishimire, Joanna Parkinson, Maria Heijer, Tadeusz Pawlik, Judith Hartleib-Geschwindner, Maria Leonsson-Zachrisson, Hans Ericsson","doi":"10.1002/bcp.70670","DOIUrl":"10.1002/bcp.70670","url":null,"abstract":"<p><strong>Aim: </strong>Balcinrenone (previously AZD9977) is a novel selective non-steroidal mineralocorticoid receptor antagonist (MRA) with a differential mechanism of action relative to approved MRAs. The aim of this trial was to assess the pharmacokinetics, safety and tolerability of balcinrenone in participants with mild and moderate hepatic impairment versus participants with normal hepatic function.</p><p><strong>Methods: </strong>Participants with mild and moderate hepatic impairment (Child-Pugh Class A [n = 8] and Child-Pugh Class B [n = 8]) were compared with group matched controls with normal hepatic function [n = 9]. Eligible participants received a single oral dose of 50-mg balcinrenone. Blood and urine samples were collected. Safety and tolerability were monitored.</p><p><strong>Results: </strong>In participants with mild hepatic impairment, balcinrenone exposure (area under the plasma concentration-time curve [AUC] and maximum plasma concentration [C_max]) was similar compared with participants with normal hepatic function. In participants with moderate hepatic impairment, C_max was similar, but there was a slight and statistically significant 30% (90% CI 4%-61%) increase in AUC compared with participants with normal hepatic function. Balcinrenone was well tolerated. All reported adverse events were of mild to moderate intensity.</p><p><strong>Conclusions: </strong>Compared with participants with normal hepatic function, balcinrenone exposure was similar in participants with mild hepatic impairment. AUC, but not C_max, was slightly increased in participants with moderate hepatic impairment. We do not consider the minor AUC increase seen in participants with moderate hepatic impairment to be clinically relevant. Thus, we would not recommend any dose adjustment for patients with mild or moderate hepatic impairment.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3656-3665"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374676","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":"Effect of esomeprazole on the pharmacokinetics of vepdegestrant, a PROteolysis TArgeting Chimera oestrogen receptor degrader, in healthy participants.","authors":"Lana Tran, Naihan Chen, Jennifer A Winton, Kyle T Matschke, Smita P Goodman, Kimberly C Lee, Yuanyuan Zhang, Weiwei Tan","doi":"10.1002/bcp.70636","DOIUrl":"10.1002/bcp.70636","url":null,"abstract":"<p><strong>Aims: </strong>The aim of this study is to evaluate the effects of multiple doses of esomeprazole, a strong proton pump inhibitor and acid-reducing agent, on the pharmacokinetics and safety of vepdegestrant, a PROteolysis TArgeting Chimera oestrogen receptor degrader.</p><p><strong>Methods: </strong>This was a Phase 1, open-label, two-period, crossover, single-dose study in healthy adult participants. During Period 1, on Day 1, a single oral dose of vepdegestrant 200 mg was administered with a moderate-fat meal following overnight fasting. During Period 2, esomeprazole 40 mg was administered once daily on Days 1-5; a single dose of vepdegestrant 200 mg was given with a moderate-fat meal on Day 5 following esomeprazole 40 mg. Serial blood samples for vepdegestrant pharmacokinetics and safety laboratory analyses were collected predose and up to 168 h after vepdegestrant dosing in each period. Safety was monitored throughout the study.</p><p><strong>Results: </strong>Twelve participants were enrolled and treated. Following administration of vepdegestrant with (test) and without (reference) esomeprazole, test/reference ratios (90% CIs) of the adjusted geometric means for vepdegestrant area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration were 83.73% (76.32, 91.86) and 74.11% (63.47, 86.52), respectively. Similar decreases in ARV-473 (vepdegestrant epimer) plasma exposure were observed. All 12 treatment-emergent adverse events experienced by seven participants were mild in severity.</p><p><strong>Conclusion: </strong>Coadministration of multiple daily doses of esomeprazole 40 mg with vepdegestrant 200 mg under fed conditions in healthy adult participants resulted in mild decreases in vepdegestrant plasma exposure. Vepdegestrant 200 mg was well tolerated in healthy adult participants.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3477-3484"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270342","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}