British journal of clinical pharmacology最新文献

{"title":"Feasibility and population exposure of 5-fluorouracil using therapeutic drug monitoring (PREDICT-5FU): A multicentre clinical trial.","authors":"Sarah Glewis, Michael Michael, Howard Gurney, Ian Olver, Nicholas Zdenkowski, Stephen Ackland, Craig Kukard, Madawa Jayawardana, S Sandun M Silva, Marliese Alexander, Jeanne Tie, Peter Galettis, Jennifer H Martin","doi":"10.1002/bcp.70006","DOIUrl":"https://doi.org/10.1002/bcp.70006","url":null,"abstract":"<p><strong>Aim: </strong>PREDICT-5FU aimed to document 5-fluorouracil (5FU) exposure in a cancer population and to evaluate the feasibility of 5FU and capecitabine therapeutic drug monitoring (TDM) in patients receiving standard doses and schedules.</p><p><strong>Methods: </strong>Multicentre, prospective, observational single-arm study. Eligible adult patients received 5FU (infusional ≥24 h) or capecitabine. Patients were treated for gastrointestinal, breast and head-and-neck cancers at four Australian hospitals. TDM was performed in consecutive cycles until target area under the curve (AUC) was reached. Pharmacogenetic testing was performed for all patients.</p><p><strong>Results: </strong>Fifty patients (24 males, 26 females) were recruited. Median age was 63 years; common diagnoses were lower gastrointestinal cancers 40% (20/50) and metastatic disease 80% (40/50). The majority received 5FU (38/50, 76%) over 46 h. Only 36% of 5FU patients achieved target AUC when dosed based on body surface area; 61% were below and 3% above target range. Post TDM-adjusted dosing, target AUC was achieved in 58% of patients (22% absolute increase vs. BSA dosing, p = 0.03), within median three cycles (range 1-5). DPYD variant allele carriers (3/4) had upfront reduced dosing due to heterozygosity; all were below the target AUC and one experienced Grade 3 toxicity. There was no correlation between dihydrouracil: uracil ratio [UH2/U] or uracilemia [U] and DPYD genotype. TDM results were reported with an average of 4 days from sampling.</p><p><strong>Conclusion: </strong>TDM dosing is feasible and increases the proportion of patients reaching target AUC. Findings are relevant across all cancers treated with 5FU, and particularly for DPYD variant allele carriers receiving upfront dose reductions.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482162","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":"Academic development of advanced therapies-How to foster their future in the clinic.","authors":"Ana Hidalgo-Simon, Caroline Pothet, Emer Cooke, Steffen Thirstrup","doi":"10.1002/bcp.70024","DOIUrl":"https://doi.org/10.1002/bcp.70024","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466977","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":"Acute cardiovascular effects associated with the use of prescription medications: A Danish nationwide screening study.","authors":"Saad Hanif Abbasi, Lars Christian Lund, Jesper Hallas, Martin Thomsen Ernst, Anton Pottegård","doi":"10.1002/bcp.16406","DOIUrl":"https://doi.org/10.1002/bcp.16406","url":null,"abstract":"<p><strong>Aim: </strong>This study aims to conduct a hypothesis-generating screening for acute cardiovascular effects of prescription medications.</p><p><strong>Methods: </strong>This Danish nationwide screening study was conducted among incident cases of cardiovascular diseases, including myocardial infarction (MI), ischemic stroke (IS), heart failure (HF), venous thromboembolism (VTE), myocarditis, and atrial fibrillation (AF), between January 2000 and December 2022. Using a case-crossover study design, we examined exposure to individual drugs on the date of the cardiovascular event (focal date) and three reference dates corresponding to days -180, -270 and -360 prior to index date. We calculated odds ratios (ORs) with 95% credible intervals (CIs) for associations between exposure drug and cardiovascular outcomes using the conditional logistic regression with a weak Bayesian shrinkage.</p><p><strong>Results: </strong>After applying exclusion criteria, we identified 191,979 cases of AF, 145,148 cases of MI, 132,271 cases of IS, 71,821 cases of HF, 16,127 cases of VTE and 10,045 cases of myocarditis. Based on the threshold for the strength of associations (OR ≥ 1.5; lower limit of CI ≥ 1), we identified 222 associations for 104 individual drugs across all six outcomes. Some major drug classes, such as antibiotics, analgesics and corticosteroids, consistently demonstrated associations for most cardiovascular outcomes. Use of pantoprazole, in contrast to other PPIs, was associated with AF (OR 1.83; 95% CI 1.68-2.00) along with MI, HF, myocarditis and VTE. Similarly, oxazepam stood out among other benzodiazepines and demonstrated increased risk of VTE (OR 2.53; 95% CI 1.55-4.13) as well as MI, HF and AF.</p><p><strong>Conclusions: </strong>The results highlight several potentially important associations across various pharmacological drug classes that warrant further investigation in tailored pharmacoepidemiological analyses.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466979","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":"Investigating started sample size, completed sample size and drop-out rate in 10 252 phase III clinical trials: Insights from ClinicalTrials.gov.","authors":"Henian Chen, Jinyong Pang, Yayi Zhao, Biwei Cao, Matthew J Valente, Weiliang Cen, Elena Valkanova","doi":"10.1002/bcp.70023","DOIUrl":"https://doi.org/10.1002/bcp.70023","url":null,"abstract":"<p><strong>Aims: </strong>This study investigated the started sample size, completed sample size and drop-out rate of 10 252 published and unpublished phase III clinical trials registered on ClinicalTrials.gov over the past 20 years.</p><p><strong>Methods: </strong>We conducted a comprehensive search on ClinicalTrials.gov for all phase III clinical trials with registered results before 26 May 2023. We retrieved and downloaded 10 252, which covered a period of more than 20 years.</p><p><strong>Results: </strong>Out of the 10 252 trials analysed, 889 (8.7%) were sponsored by the US National Institutes of Health/US Federal agencies (NIH/US Fed), 8429 (82.2%) were sponsored by industry. The overall median started sample size was 302. The overall median completed sample size was 228. The median completed sample sizes were 258 for industry-sponsored trials, and 194 for NIH/US Fed-sponsored trials. The median completed sample sizes were 321 for biological interventions and 223 for drug interventions. The overall median drop-out rate was 11%. Statistically significant differences were observed in sample sizes between industry-sponsored trials and NIH/US Fed-sponsored trials (P < 0.0001). Neither the started sample sizes nor the completed sample sizes have shown any change over the course of the past 20 years.</p><p><strong>Conclusions: </strong>Our findings indicate that a majority of the analysed trials lack sufficient statistical power (80%) to detect small effect sizes, and approximately half of the trials did not have 80% power to detect medium effect sizes. Notably, trials funded by NIH/US Fed exhibit significantly smaller sample sizes compared to trials sponsored by industry. When conducting sample size calculations for clinical trials, it is crucial to consider the anticipated effect size, variability and drop-out rate.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466981","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":"Population pharmacokinetics and dosing of dispersible moxifloxacin formulation in children with rifampicin-resistant tuberculosis.","authors":"Megan Palmer, Yuanxi Zou, Anneke C Hesseling, Louvina van der Laan, Ingrid Courtney, Aarti A Kinikar, Naresh Sonkawade, Mandar Paradkar, Vandana Kulkarni, Dessa Jean O Casalme, Melchor V G Frias, Heather Draper, Lubbe Wiesner, Mats O Karlsson, Paolo Denti, Elin M Svensson, Anthony J Garcia-Prats","doi":"10.1002/bcp.70005","DOIUrl":"https://doi.org/10.1002/bcp.70005","url":null,"abstract":"<p><strong>Aims: </strong>Moxifloxacin is a priority drug for treating rifampicin-resistant tuberculosis (RR-TB). We assessed the pharmacokinetics of a child-friendly, dispersible 100 mg tablet moxifloxacin formulation (dispersed in water) compared to the standard 400 mg non-dispersible formulation (crushed and suspended in water) in children and evaluated current dosing recommendations.</p><p><strong>Methods: </strong>The CATALYST trial investigated the pharmacokinetics of moxifloxacin in children with RR-TB. Children were enrolled in South Africa, India and the Philippines. Intensive pharmacokinetic sampling was undertaken while children were taking the standard non-dispersible 400 mg moxifloxacin tablet formulation and repeated after switching to the novel dispersible formulation. Pharmacokinetic data were analysed using population pharmacokinetic modelling. Simulations were performed to evaluate moxifloxacin exposures in children compared to consensus adult reference exposures using current World Health Organization (WHO)-recommended doses and more recent model-based doses.</p><p><strong>Results: </strong>Thirty-six children were enrolled [median age 4.8 (range 0.4-15) years and weight 15.6 (range 6.9-42.1) kg]. A two-compartment disposition model with first-order elimination and delayed absorption was developed. The bioavailability of dispersible versus standard formulations fulfilled standard bioequivalence criterion (ratio 1.05 with 90% confidence interval 0.95-1.15). Simulations showed WHO-recommended doses achieved exposures similar to those in adults in children >10 kg, while children <10 kg may require 33%-56% higher doses to reach adult reference exposures.</p><p><strong>Conclusions: </strong>Dosing recommendations for children can be the same for the dispersible paediatric and standard non-dispersible adult moxifloxacin formulation. The current WHO dosing recommendation risks underdosing moxifloxacin in children <10 kg. We propose optimized moxifloxacin doses for both formulations.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432512","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":"Empirical dosage determination of vancomycin for a target area under the concentration-time curve of 400 μg·h/mL in the first 24 h: A prospective multicenter observational study with rich sampling.","authors":"Kazutaka Oda, Yoko Hiyama, Takashi Ueda, Hirokazu Furusho, Tomoyuki Yamada, Tomomi Katanoda, Hiroshi Yoshikawa, Takashi Tomita, Takeshi Ide, Sachiko Jingami, Yusuke Kusaka, Hirofumi Jono, Hideyuki Saito","doi":"10.1002/bcp.70002","DOIUrl":"https://doi.org/10.1002/bcp.70002","url":null,"abstract":"<p><strong>Aim: </strong>Area under the concentration-time curve (AUC)-guided dosing is recommended in vancomycin therapy. This study aims to determine the empirical dosing for achieving an AUC on the first day (AUC_f24h) and the optimal number of samplings for Bayesian estimation.</p><p><strong>Methods: </strong>A multicentric prospective study was conducted across five hospitals. Critically ill patients were included, with rich sampling conducted on the first day and/or days 3-5 of therapy. Cumulative dose on the first day for the trapezoidal AUC_f24h > 400 μg·h/mL and the predictive performances of AUC and clearance in limited sampling were evaluated. The probability of adherence to AUC_f24h within 400-600 μg·h/mL in the guidelines-compliant or non-compliant doses were also evaluated.</p><p><strong>Results: </strong>The study included 27 patients and 395 samplings were performed. The mean cumulative dose (standard deviation) on the first day was higher in the group with AUC_f24h > 400 μg·h/mL at 49.3 (4.5) mg/kg compared to the group with AUC_f24h < 400 μg·h/mL at 42.1 (6.8) mg/kg (P = 0.01) for patients with creatinine clearance > 90 mL/min, respectively. The biases and variations of Bayesian posterior AUC by using only a trough concentration were improved by using two-point concentrations at trough and peak. The probability of adherence to AUC_f24h was significantly higher in the guidelines-compliant group (66.7%) than in the non-compliant group (11.1%, P < .01).</p><p><strong>Conclusion: </strong>This study suggested an empirical dosage of about 50 mg/kg on the first day of vancomycin therapy and the use of two-point sampling in Bayesian estimations to enhance accuracy.</p><p><strong>Trial registration: </strong>Not applicable because this is a non-intervention study.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440020","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":"Physiologically based pharmacokinetic model for oxcarbazepine active metabolite to predict pharmacokinetics in paediatric patients with renal impairment and adjust dosages.","authors":"Cheng-Jie Ke, Si-Ting Liu, Yu-Die Qian, Xiang You, Rong-Fang Lin, Cui-Hong Lin, Pin-Fang Huang, Wei-Wei Lin","doi":"10.1002/bcp.70016","DOIUrl":"https://doi.org/10.1002/bcp.70016","url":null,"abstract":"<p><strong>Aims: </strong>Oxcarbazepine (OXC) has been approved as monotherapy or adjunctive therapy for paediatric partial seizures. There are few reports on the pharmacokinetics (PK) of OXC in paediatric patients with renal impairment (RI), especially dosage studies of RI, which are rarely conducted on paediatric patients. This study aimed to predict the PK of OXC in children with RI and to provide recommendations for dose adjustment in this population.</p><p><strong>Methods: </strong>Physiologically based pharmacokinetic (PBPK) models of the active metabolites of OXC were developed and verified, and their disposition was simulated in populations with or without RI.</p><p><strong>Results: </strong>A fold error value of less than 2 was observed based on the simulated results from PBPK models for single- and multi-dose administration. Based on the predictions for paediatric patients with moderate, severe, and end-stage RI, the dose should be adjusted to 50, 40 and 25% of the normal dose, respectively, in children aged 2-5 years; and 50, 30 and 20%, respectively, in children aged 6-17 years.</p><p><strong>Conclusions: </strong>The developed PBPK model is a valuable tool for predicting the OXC dosage in paediatric patients with RI.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440040","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 severe renal impairment on the pharmacokinetics, safety and tolerability of balcinrenone.","authors":"Chandrali S Bhattacharya, Hans Ericsson, Susanne Johansson, Joanna Parkinson, Simina M Boca, Ye Yang, Maria Heijer, Greggory Housler, Maria Leonsson-Zachrisson, Judith Hartleib-Geschwindner, Patricia Ely Pizzato","doi":"10.1002/bcp.70017","DOIUrl":"https://doi.org/10.1002/bcp.70017","url":null,"abstract":"<p><strong>Aims: </strong>The aim of this phase 1 trial was to assess the pharmacokinetics, safety and tolerability of balcinrenone (previously AZD9977) in participants with severe renal impairment vs. those with normal renal function.</p><p><strong>Methods: </strong>Participants with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²) not on dialysis were compared with group-matched control participants with eGFR ≥ 90 mL/min/1.73 m². Eligible participants received a single oral dose of 150 mg balcinrenone, and blood and urine samples were collected for analysis.</p><p><strong>Results: </strong>The total apparent balcinrenone clearance was 50% lower in the severe renal impairment group, resulting in an approximately two-fold higher area under the curve (AUC) and a 1.4-fold higher maximum observed plasma concentration in the severe renal impairment group compared with the control group. The terminal half-life and plasma protein binding were similar in both groups. Balcinrenone was safe and well tolerated in all participants. All reported adverse events were of mild-to-moderate severity and not considered related to balcinrenone.</p><p><strong>Conclusions: </strong>Balcinrenone exposure was approximately two-fold higher in participants with severe renal impairment compared with the group-matched control participants. Based on linear regression analysis of total apparent balcinrenone clearance vs. baseline eGFR, the AUC exposure is predicted to be <50% higher in patients with an eGFR of 20 mL/min/1.73 m² compared with those with an eGFR of 60 mL/min/1.73 m². In light of these findings, no dose adjustment based on eGFR is needed in two ongoing studies that target these patients (MIRO-CKD [NCT06350123] and BalanceD-HF [NCT06307652]).</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440104","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":"Spotlight commentary: Innovations in clinical trials.","authors":"Nataša Hudej, Matea Radačić Aumiler","doi":"10.1002/bcp.70010","DOIUrl":"https://doi.org/10.1002/bcp.70010","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440099","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":"Drug reaction with eosinophilia and systemic symptoms induced by paclitaxel, a rare combination.","authors":"Mathieu Lagassy, Mathilde Barthelemy, Camille Kieffer, Charlene Boulay, Delphine Bourneau-Martin, Gwenaëlle Veyrac, Audrey Lafon, Olivia Bauvin, Laetitia Augusto-Pelegrin, Alexis Lefebvre, Florence Tetart","doi":"10.1002/bcp.70012","DOIUrl":"https://doi.org/10.1002/bcp.70012","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432475","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}