British journal of clinical pharmacology最新文献

{"title":"Population pharmacokinetics and exposure-response relationships of dostarlimab in primary advanced or recurrent endometrial cancer in part 1 of RUBY.","authors":"Mita Kuchimanchi, Trine Lembrecht Jørgensen, Eva Hanze, Thierry André, Angela Jain, Dominique Berton, Oskar Alskär, Oleksandr Zub, Ana Oaknin, Mark S Shahin, Anthoula Koliadi, Bhavana Pothuri, Tom Krivak, Mikalai Pishchyk, Yakir Segev, Floor J Backes, Christine Gennigens, Sara Bouberhan, Stefan Zajic, Murad Melhem, Joseph Buscema","doi":"10.1111/bcp.16325","DOIUrl":"https://doi.org/10.1111/bcp.16325","url":null,"abstract":"<p><strong>Aims: </strong>Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure-efficacy/safety (ER) relationships.</p><p><strong>Methods: </strong>A PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure-safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure-efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression-free survival (PFS).</p><p><strong>Results: </strong>For the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure-safety or exposure-PFS relationships.</p><p><strong>Conclusions: </strong>The addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure-safety or exposure-PFS relationships.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614404","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":"SLCO1B1 variants in a patient of African ancestry presenting with rosuvastatin-induced rhabdomyolysis: A case report.","authors":"Samantha Medwid, Rowan Deckert, Steven E Gryn, Richard B Kim","doi":"10.1111/bcp.16329","DOIUrl":"https://doi.org/10.1111/bcp.16329","url":null,"abstract":"<p><p>We report a case of an adult woman of African ancestry who was hospitalized with statin induced- rhabdomyolysis. The patient presented to the emergency room with a 2-week history of worsening muscle pain, nausea, vomiting and low oral intake, 1 month after starting 40 mg daily dose of rosuvastatin. Sequencing of SLCO1B1 coding regions revealed the patient was heterozygous for two SLCO1B1 deleterious variants, c.481+1G>T and c.1463G>C (*9), which are more prevalent in patients of African ancestry. This highlights the importance of pharmacogenetic testing in SLCO1B1, which includes a broader range of genetic variants for patients of African ancestry.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603339","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":"Physicians' and pharmacists' perspective on clarity and clinical relevance of absolute contraindications in \"Summaries of Product Characteristics\".","authors":"Wahram Andrikyan, Michael I Sponfeldner, Lea Jung-Poppe, Pauline Dürr, Melanie I Straubmeier, Anna K Schuster, Laura Weisbach, Katrin Farker, Michael Hartmann, Martin F Fromm, Renke Maas","doi":"10.1111/bcp.16331","DOIUrl":"https://doi.org/10.1111/bcp.16331","url":null,"abstract":"<p><strong>Aims: </strong>Previous work has identified several limitations in \"Summaries of Product Characteristics\" (SmPCs), which are associated with risks for patients. The aim of this study was to evaluate pharmacists' and physicians' interpretation of contraindications in SmPCs and reasons for their nonadherence in clinical routine.</p><p><strong>Methods: </strong>For 20 commonly missed or ignored absolute contraindications, an anonymous online survey providing 24 clinical example cases (one or two per contraindication) for physicians and pharmacists was developed. Experts in medication safety were asked whether the respective case fulfilled the definition of the contraindication in the SmPC: (a) formally, irrespective of the clinical relevance of the contraindication (17 cases), and (b) whether the contraindication was deemed clinically relevant in each respective case (24 cases).</p><p><strong>Results: </strong>Twenty-seven pharmacists and 27 physicians completed the survey. For only one case (1/17; 5.8%) did all experts agree on the same answer option regarding the formal fulfilment of a given contraindication statement. Experts gave heterogeneous answers regarding the interpretation of a contraindication. For instance, among 10 predefined answer options for the contraindication \"active liver disease\" in the SmPC of simvastatin, every option was selected by at least six experts. In 17/24 (70.8%) clinical example cases a majority of experts agreed on the clinical relevance of a given contraindication. Key reasons for nonadherence to contraindications were \"patient monitoring possible\", \"lack of alternative treatment\" and \"acute/severe situations\".</p><p><strong>Conclusions: </strong>Experts' disagreement on the interpretation of contraindications in SmPCs using clinical example cases indicates that further efforts are needed to improve their usability in clinical routine.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603432","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":"Progress in geriatric pharmacology: Improving drug development, evaluation and use for ageing populations.","authors":"Sarah N Hilmer, Danijela Gnjidic","doi":"10.1111/bcp.16330","DOIUrl":"https://doi.org/10.1111/bcp.16330","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582150","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":"Enlarged choroid plexus related to atrophy of hippocampal subfield volumes and glymphatic dysfunction in benzodiazepine use disorder.","authors":"Yang Zhou, Meizhi Yi, Xun Li, Tianyao Wang, Yihong Jiang, Luokai Zhang, Jun Hu, Huiting Wu, Wei Zou, Jun Liu, Hong Zhou","doi":"10.1111/bcp.16328","DOIUrl":"https://doi.org/10.1111/bcp.16328","url":null,"abstract":"<p><strong>Aims: </strong>The aim of this study was to explore the relationship of choroid plexus (CP) volume with hippocampal subregion volume and glymphatic system in patients with benzodiazepine use disorders (BUD).</p><p><strong>Methods: </strong>Eighty-four participants were recruited including 23 patients with BUD, 29 patients with chronic insomnia (CI) and 32 healthy controls (HC). The morphological alterations in CP, hippocampal subfield volumes and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index were compared between the three groups and the relationships between CP volume and hippocampal subfield volumes and the glymphatic system were further investigated.</p><p><strong>Results: </strong>Compared with the HC individuals, the CP volumes augmented and hippocampal subfield volumes reduced in patients with BUD (P < .05) but not in patients with CI (P > .05). In patients with BUD, there were extensive relationships between augmented CP volume and decreased hippocampal subfield volumes (P < .05, r = -0.421--0.513). CP volume was negatively related with the DTI-ALPS index (r = -0.582, P = .004) within the BUD group. In patients with BUD, the volume of bilateral cornu ammonis (CA)1 body, molecular layer (ML) body, hippocampal tail, left CA1 head volumes, right dentate gyrus body volumes, and right CA4 body volumes were positively related with the Montreal Cognitive Assessment scores (P < .05, r = 0.422-0.683). Right CA1 and ML body volumes positively related with the Mini-Mental State Examination scores (P < .05, r = 0.503-0.575).</p><p><strong>Conclusions: </strong>The enlarged CP related to atrophy of hippocampal subfield volumes and the glymphatic system dysfunction were shown in BUD patients.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582146","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":"Issue Highlights","authors":"","doi":"10.1111/bcp.16322","DOIUrl":"https://doi.org/10.1111/bcp.16322","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 11","pages":"2699"},"PeriodicalIF":3.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541030","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":"Feasibility of dried blood spot collection for caffeine pharmacokinetic studies in microgravity: Insights from parabolic flight campaigns.","authors":"Audrey Derobertmasure, Li Shean Toh, Céline Verstuyft, Srboljub Lukic, Christelle De Sousa Carvalho, Raphaël Couronné, Marie Beauvalet, Stéphanie Chhun, Pierre Boutouyrie","doi":"10.1111/bcp.16320","DOIUrl":"https://doi.org/10.1111/bcp.16320","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims: &lt;/strong&gt;Therapeutic drug monitoring for astronauts faces limitations in conventional blood sampling and sample management onboard the international space station. Here, we explore the feasibility of dried blood spot (DBS) collection during parabolic flights (PF) to overcome these constraints.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We assessed the feasibility of blood deposition on blotting paper for preanalytical aspects in a PF using synthetic blood. Subsequently, DBS sampling validation was carried out in another PF campaign. Twenty volunteers participated in a pharmacokinetic study on caffeine and its metabolite, paraxanthine, conducted during parabolic flights. After &gt;18 h caffeine washout, coffee (115 mg), tea (30 mg) or dark chocolate (11 mg) were ingested by the participants. DBS samples were collected at baseline, during weightlessness and post-flight. Caffeine and paraxanthine were analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Genotyping for cytochrome P450-1A2 (CYP1A2) was performed and a metabolic ratio by area under the curve for caffeine and paraxanthine (AUC&lt;sub&gt;PAX&lt;/sub&gt;/AUC&lt;sub&gt;CAF&lt;/sub&gt;) for CYP1A2 was determined. A user experience survey was also conducted.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Full in-flight pharmacokinetic study was feasible in seventeen volunteers with three unable to perform the sampling due to motion sickness. Nineteen participants (twelve males and seven females) completed pharmacokinetic profiles, with repeated pharmacokinetic studies for six participants. CYP1A2 genotyping resulted in eight ultrarapid, eleven intermediate, and one poor metabolizer. Among the women, four were on oestrogen contraceptives, a known inhibitor of CYP1A2, and were considered as poor metabolizers. Expected differences in kinetic profiles, consistent with consumption habits, the ingested dose and the genotypic/phenotypic information, were observed. The mean caffeine AUC for coffee, tea and chocolate were 9419 ng.h.mL&lt;sup&gt;-1&lt;/sup&gt; (95% confidence interval [CI]: 6222-12 616, n = 10), 6917 ng.h.mL&lt;sup&gt;-1&lt;/sup&gt; (95% CI: 2729-11 105), n = 7) and 3039 ng.h.mL&lt;sup&gt;-1&lt;/sup&gt; (95% CI: 1614-4142, n = 12), respectively. The mean paraxanthine AUC were 10 566 ng.h.mL&lt;sup&gt;-1&lt;/sup&gt; (95% CI: 6242-14 890, n = 10), 4011 ng.h.mL&lt;sup&gt;-1&lt;/sup&gt; (95% CI: 2305-5716, n = 7) and 3638 ng.h.mL&lt;sup&gt;-1&lt;/sup&gt; (95% CI: 1589-40 859, n = 12), respectively. The mean metabolic ratio in oestrogen-treated women was 0.53 (95% CI: 0.35-0.71) compared to 1.19 (95% CI: 0.99-1.33) in others. The mean metabolic ratio was 1.02 (95% CI: 0.81-1.23, n = 15) on the ground and 1.10 (95% CI: 0.70-1.41, n = 13) during the parabolic flights, with no significant difference observed between the two conditions. Overall participants were satisfied with the usability of the method.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;DBS collection was safe, stable, feasible and well accepted in weightlessness. This method would offer valuable insights into human metaboli","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543822","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":"Effects of age, sex, daily dose, comorbidity and co-medication on venlafaxine-associated cardiovascular adverse events: A pharmacovigilance analysis of the FDA Adverse Event Reporting System database.","authors":"Zhanzhang Wang, Haoyang Lu, Yuandan Li, Shanqing Huang, Ming Zhang, Yuguan Wen, Dewei Shang","doi":"10.1111/bcp.16326","DOIUrl":"https://doi.org/10.1111/bcp.16326","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to provide a comprehensive view of cardiovascular adverse events (AEs) associated with venlafaxine (VEN) therapy.</p><p><strong>Methods: </strong>Cardiovascular AE reports for patients receiving VEN therapy were retrieved from January 2004 to December 2023 from the FDA Adverse Event Reporting System database. Effects of age, sex and daily VEN dose on the occurrence of different types of cardiovascular AEs and the influence of demographics, VEN dose, comorbidity and co-medication on death in patients with cardiovascular AEs were analysed by multivariate logistic regression analysis.</p><p><strong>Results: </strong>The study included 16 110 AE reports following VEN treatment (median age: 51 years, females: 69.78%, median VEN daily dose: 100 mg/day). VEN daily dose was associated with increased risks of cardiac arrhythmias, embolic and thrombotic events, torsade de pointes/QT prolongation, ischaemic heart disease, cardiac failure, cardiomyopathy and overall cardiovascular events. The elderly (≥ 75 years), male sex, comorbidity (infections and infestations, cardiac disorders, nervous system disorders) and co-medication (quetiapine and clozapine) were related to death following VEN-associated cardiovascular AEs; however, the risk of cardiovascular death did not increase with regular VEN doses.</p><p><strong>Conclusions: </strong>Our study confirmed the association of cardiovascular AEs with VEN therapy and revealed the influencing factors for the risk of VEN-related cardiovascular AEs and death due to these events. Based on the obtained evidence, the cardiovascular health of late-elderly patients with complex comorbidity and polytherapy should be closely monitored when they receive VEN therapy. As an exploratory study, prospective studies are needed to validate our findings in the future.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543821","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":"Letter to the editor: Personalized antihypertensive treatment-The role of body fat indices beyond body mass index.","authors":"Christina Antza, Andrej Belančić, Ana Jelaković","doi":"10.1111/bcp.16332","DOIUrl":"https://doi.org/10.1111/bcp.16332","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521003","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":"Review of the fluoropyrimidine antidote uridine triacetate.","authors":"Jack T Thompson, David M Wood, Paul I Dargan","doi":"10.1111/bcp.16319","DOIUrl":"https://doi.org/10.1111/bcp.16319","url":null,"abstract":"<p><p>In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose. A lack of clinical equipoise meant a placebo-controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521004","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}