British journal of clinical pharmacology最新文献

{"title":"Advising patients on serotonin syndrome in General Practice","authors":"Theo Boheimer,&nbsp;Harish Thampy","doi":"10.1111/bcp.16240","DOIUrl":"10.1111/bcp.16240","url":null,"abstract":"<p>We were very interested in the review of serotonin syndrome management by Chiew et al.<span>¹</span> It highlighted the importance of early symptom recognition in reducing severity progression.</p><p>Given that the majority of prescribing practices occur in primary care, we recently conducted an audit (April 2024) at a large General Practice in the United Kingdom. The audit aimed to determine whether the potential risk of serotonin syndrome was communicated to at-risk patients and, if so, the nature of the advice provided. We performed a search of the practice's electronic patient records to identify patients who were currently co-prescribed two or more medications known to increase the risk of serotonin syndrome. The medications of interest included selective serotonin reuptake inhibitors, serotonergic-noradrenergic reuptake inhibitors, triptans and opioids. A subsequent review of individual patient notes was conducted to identify any documentation pertaining to serotonin syndrome counselling.</p><p>From the total practice population of 15 328 patients, 148 individuals were identified through the search. Of these, only 36 patients (24%) had documented evidence of receiving specific safety netting advice regarding serotonin syndrome. Among these, 5 patients were informed solely of the risk of the condition, 18 were additionally warned about the potential signs and symptoms and 13 were advised on appropriate actions to take if they experienced these symptoms.</p><p>We acknowledge that this audit is limited by its reliance on clinical documentation, which may not fully capture all discussions that occurred during consultations. However, from a medico-legal perspective, the absence of documentation generally implies that the discussion did not take place. Therefore, this audit underscores the need to enhance medication counselling practices, particularly concerning higher risk drug combinations, to ensure that patients are adequately informed about the possible signs and symptoms of serotonin syndrome and the importance of seeking urgent medical attention.</p><p>As a result of this audit, we recommend the implementation of educational interventions to raise clinician awareness of this complication. Additionally, integrating alerts into the patient record system may help remind clinicians of the key areas to discuss and document during consultations. A follow-up audit is planned to evaluate the effectiveness of these interventions.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307064","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":"Concentration-QTc analysis of soticlestat in healthy adults: An alternative to a thorough QT study.","authors":"Wei Yin, Nobuhito Dote, Hiroyuki Fukase, Manami Imazaki, Kohei Shimizu, Shinichi Takeda, Borje Darpo, Hongqi Xue, Mahnaz Asgharnejad","doi":"10.1111/bcp.16255","DOIUrl":"https://doi.org/10.1111/bcp.16255","url":null,"abstract":"<p><strong>Aim: </strong>This study aimed to examine the cardiac and overall safety and pharmacokinetic (PK) profiles of soticlestat (TAK-935), an oral, first-in-class selective cholesterol 24-hydroxylase inhibitor.</p><p><strong>Methods: </strong>Data came from a randomised, phase 1 study of soticlestat in 33 healthy Japanese adults (NCT04461483); 24 adults in Part 1 (single-dose soticlestat 200-1200 mg or placebo) and 9 in Part 2 (soticlestat 100-300 mg twice daily or placebo for 21 days). PK sample collection was paired with 12-lead electrocardiogram data from continuous Holter recordings. The concentration-QTc relationship was analysed using a linear mixed-effects model. QTc prolongation safety margins were determined for two scenarios of calculated high clinical exposures: scenario 1 (NCT05064449) involved coadministration of single-dose soticlestat 300 mg with itraconazole or mefenamic acid and scenario 2 (NCT05098054) involved single-dose soticlestat 300 mg administration in participants with mild/moderate hepatic impairment (implementing a 3-fold dose reduction for moderate severity).</p><p><strong>Results: </strong>Based on concentration-QTc analysis, placebo-corrected change-from-baseline QT values (90% confidence intervals), corrected for heart rate (Fridericia's method), were 0.94 ms (-2.35, 4.23) for soticlestat and 0.63 ms (-3.15, 4.41) for its N-oxide metabolite plasma concentrations at therapeutic doses (soticlestat 300 mg twice daily); safety margins were >2-fold for scenarios of calculated high clinical exposures. No (Part 1) and five (83.3%; Part 2) participants experienced treatment-emergent adverse events (all mild).</p><p><strong>Conclusion: </strong>There was no evidence for QT prolongation with soticlestat at therapeutic doses or in two scenarios of high clinical exposures, which resulted in regulatory agencies waiving requirements of a thorough QT study. Safety/PK findings aligned with previous soticlestat clinical studies.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307065","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":"Exposure-response relationships of mirvetuximab soravtansine in patients with folate receptor-α-positive ovarian cancer: Justification of therapeutic dose regimen.","authors":"Ya-Ping Tu, H Maxime Lagraauw, Michael Method, Yuemei Wang, Eva Hanze, Lingling Li, Timothy Parrott, Callum M Sloss, Eric H Westin","doi":"10.1111/bcp.16250","DOIUrl":"https://doi.org/10.1111/bcp.16250","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to investigate exposure-response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first-in-class antibody-drug conjugate approved for the treatment of folate receptor-α-positive platinum-resistant ovarian cancer.</p><p><strong>Methods: </strong>MIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV-treated patients (n = 215) in a recent confirmatory, randomized, chemotherapy-controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n = 757).</p><p><strong>Results: </strong>In the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression-free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration-time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV.</p><p><strong>Conclusion: </strong>The trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280514","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":"Calcium channel blocker overdose: Not all the same toxicity.","authors":"Geoffrey K Isbister, Shane Jenkins, Keith Harris, Michael A Downes, Katherine Z Isoardi","doi":"10.1111/bcp.16258","DOIUrl":"https://doi.org/10.1111/bcp.16258","url":null,"abstract":"<p><strong>Aims: </strong>Calcium channel blocker (CCB) overdose remains an important poisoning, with increasing availability of dihydropyridines. We aimed to compare the severity and treatment of CCB overdoses.</p><p><strong>Methods: </strong>We reviewed CCB overdoses presenting to two toxicology services from 2014 to 2023. We extracted prospectively collected data from a clinical database, including demographics, dose, co-ingestants, complications, treatments and outcomes, to compare different CCBs.</p><p><strong>Results: </strong>There were 236 overdoses; median age 55 years (interquartile range [IQR]: 41-65 years); 130 (55%) were females. Dihydropyridine overdoses increased significantly: median of nine cases annually (IQR: 8.8-12.3) during the study compared to a median of three cases annually (IQR: 1-4.3; P < 0.001) in the 10 years prior. The commonest agent was amlodipine (147), then lercanidipine (28), diltiazem (27), verapamil (23) and felodipine (11). Median defined daily dose ingested was higher for dihydropyridines, and cardiac co-ingestants were common except verapamil. Median length of stay was 21 h (IQR: 13-43 h), which was similar except longer for diltiazem (median, 39 h). Fifty-six patients (24%) were admitted to intensive care, more often for diltiazem (14; 52%) and verapamil (7; 30%). Dysrhythmias occurred in 19 patients (diltiazem [9], verapamil [8], amlodipine [2]), and included 13 junctional dysrhythmias. Hypotension occurred in 91 patients (39%), 62 (26%) received inotropes/vasopressors (adrenaline 32 [52%], noradrenaline 48 [77%]), 21 (9%) high-dose insulin and 44 (19%) calcium. Adrenaline and high-dose insulin were more commonly given in diltiazem and verapamil overdoses, compared to vasopressors in dihydropyridine overdoses. Acute kidney injury occurred in 39 patients. Seven (3%) patients died.</p><p><strong>Conclusions: </strong>Dihydropyridines were the commonest CCB overdoses, with amlodipine making up half. More severe toxicity occurred with diltiazem and verapamil.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280513","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 association between use of proton pump inhibitors and frailty index among middle-aged and older adults.","authors":"Rui Wu, Guojun Hong, Xiankun Cheng, Yue Zhu","doi":"10.1111/bcp.16260","DOIUrl":"https://doi.org/10.1111/bcp.16260","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to investigate the association between use of proton pump inhibitors (PPI) and frailty index (FI), and to assess the causality relationship using Mendelian randomization (MR).</p><p><strong>Methods: </strong>A total of 9756 middle-aged and older adults from the National Health and Nutrition Examination Survey were included. The FI was evaluated using a previously validated 49-item deficit model to assess frailty status, which is one of the common approaches to measure overall health burden. We performed weighted multivariable-adjusted linear regression to assess the association between PPI use and FI, and conducted a two-sample MR to evaluate causality, employing various sensitivity analyses for robustness. The inverse variance weighted (IVW) method was used as the primary analysis.</p><p><strong>Results: </strong>Multiple linear regression analysis revealed a positive association between PPI use and FI (β = 0.048, 95% confidence interval [CI]: 0.042-0.054, P < .001). This association was observed in both short-term (≤ 1 year) and long-term (> 1 year) PPI users (P for trend < 0.001). The MR study also revealed a positive association between PPI use and FI based on the IVW method (β = 1.183, 95% CI: 0.474-1.892, P = .001).</p><p><strong>Conclusions: </strong>While our findings suggest a potential link between PPI use and FI, they should be interpreted with caution due to the study's limitations. Although the MR analysis suggests a causal relationship, further research, particularly longitudinal studies, is needed to confirm these findings and better establish temporality.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280515","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":"A randomized phase I study of the safety and pharmacokinetics of BI 1291583 in healthy Japanese male subjects","authors":"Yusuke Tadayasu, Donald Sarubbi, Takumi Furuichi, Anastasia Eleftheraki, Shuhei Nakamura, Wiebke Sauter, Ryuzo Hanada","doi":"10.1111/bcp.16249","DOIUrl":"https://doi.org/10.1111/bcp.16249","url":null,"abstract":"Bronchiectasis patients face an unmet need for treatment options that reduce inflammation. Cathepsin C inhibition is expected to achieve this by reducing the activation of neutrophil-derived serine proteases. Here, we present safety and pharmacokinetic (PK) data from a Phase I trial evaluating the novel cathepsin C inhibitor BI 1291583 in healthy Japanese male subjects.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254420","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":"Comparing regulatory guidance on risk minimization/mitigation and the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies checklist","authors":"Sonia Guleria, Emily Brouwer, David A. Brown, Katja M. Hakkarainen","doi":"10.1111/bcp.16259","DOIUrl":"https://doi.org/10.1111/bcp.16259","url":null,"abstract":"The latest country-specific regulatory guidance for assessing effectiveness of risk minimization measures (RMM) strategies was identified across five continents—Africa (Egypt, South Africa), Asia (Australia, China, Japan, South Korea, Singapore), Europe (EU-27, United Kingdom), North America (Unites States, Canada) and South America (Brazil)—and compared to the Reporting recommendation Intended for pharmaceutical Risk Minimization Evaluation Studies (RIMES) checklist, developed to assess the quality of effectiveness evaluations and endorsed by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). RIMES checklist items address study hypothesis, participants, measures, statistical analysis and results. European Medical Agency (EMA) and Food and Drug Administration (FDA) guidance only partially aligned with RIMES, primarily for measures and results. In the absence of country-specific guidance, most countries recommended following EMA or FDA guidelines; Japan and South Africa mentioned the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH E2E) guideline; Brazil and China had no guidance/recommendations. Worldwide, there was a lack of RMM-specific guidance and, when guidance existed, they were not harmonized, and alignment with the RIMES checklist was limited.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254422","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 codeine rescheduling on prescribing of codeine and other opioids: Interrupted time series analyses using Australian general practice data","authors":"Helena Cangadis-Douglass, Ting Xia, J. Simon Bell, Suzanne Nielsen","doi":"10.1111/bcp.16246","DOIUrl":"https://doi.org/10.1111/bcp.16246","url":null,"abstract":"We aimed to determine the impact of codeine rescheduling on prescribing of codeine and other opioids, with a focus on demographic and diagnoses associated with codeine prescribing before and after rescheduling of codeine to prescription-only in February 2018.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254421","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":"Incorporating the One Health Philosophy into pharmacovigilance: Ecopharmacovigilance","authors":"Montserrat García,&nbsp;Jerin Jose Cherian,&nbsp;Unax Lertxundi","doi":"10.1111/bcp.16254","DOIUrl":"10.1111/bcp.16254","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254424","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":"Optimizing β‐lactam‐containing antibiotic combination therapy for the treatment of Buruli ulcer","authors":"Salvatore D'Agate, Peter Velickovic, Noelia García‐Barrios, Santiago Ramón‐García, Oscar Della Pasqua","doi":"10.1111/bcp.16209","DOIUrl":"https://doi.org/10.1111/bcp.16209","url":null,"abstract":"AimsThe current treatment for Buruli ulcer is based on empirical evidence of efficacy. However, there is an opportunity for shortening its duration and improving response rates. Evolving understanding of the pharmacokinetic–pharmacodynamic relationships provides the basis for a stronger dose rationale for antibiotics. In conjunction with modelling and simulation, it is possible to identify dosing regimens with the highest probability of target attainment (PTA). This investigation aims to: (i) assess the dose rationale for a new combination therapy including amoxicillin/clavulanic acid (AMX/CLV) currently in clinical trials; and (ii) compare its performance with alternative dosing regimens including rifampicin, clarithromycin and AMX/CLV.MethodsIn vitro estimates of the minimum inhibitory (MIC) concentration were selected as a measure of the antibacterial activity of different drug combinations. Clinical trial simulations were used to characterize the concentration <jats:italic>vs</jats:italic>. time profiles of rifampicin, clarithromycin and amoxicillin in a virtual cohort of adult and paediatric patients, considering the effect of baseline covariates on disposition parameters and interindividual variability in exposure. The PTA of each regimen was then assessed using different thresholds of the time above MIC.ResultsA weight‐banded dosing regimen including 150–600 mg rifampicin once daily, 250–1000 mg clarithromycin and AMX/CLV 22.5 mg/kg /1000 mg twice daily ensures higher PTA than the standard of care with AMX/CLV 45 mg/kg/2000 mg once daily.ConclusionThe higher PTA values support the proposed 4‐drug combination (rifampicin, clarithromycin, AMX/CLV) currently under clinical investigation. Our findings also suggest that higher rifampicin doses might contribute to enhanced treatment efficacy.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254425","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}