British journal of clinical pharmacology最新文献

{"title":"Janus kinase inhibitors for the treatment of lichen Sclerosus: A systematic review.","authors":"Chin-Hsuan Shen, Tzu-Yu Wang, Ching-Chi Chi","doi":"10.1002/bcp.70042","DOIUrl":"https://doi.org/10.1002/bcp.70042","url":null,"abstract":"<p><strong>Aim: </strong>The current treatment options for lichen sclerosus (LS) remain limited. We aimed to systematically assess the evidence on the effects of Janus kinase (JAK) inhibitors in treating LS.</p><p><strong>Methods: </strong>We performed a systematic review and searched PubMed, Cochrane, Embase and the Airiti Library from inception to 16 January 2025. As we expected a lack of relevant randomized trials, we also included relevant single-arm trials, case reports and case series. The risk of bias of included case reports and case series was evaluated using Murad's tool, while single-arm trials were assessed using Alsinbili's tool.</p><p><strong>Results: </strong>This systematic review included a total of nine studies, with one single-arm trial and three case reports on baricitinib, one single-arm trial and one case report on abrocitinib, two case reports on topical ruxolitinib and one case report on tofacitinib. A total of 43 LS patients (31 females and 12 males) were included, with four presenting with extragenital LS and one with bullous type affecting both genital and extragenital areas. The overall risk of bias of the included studies was low to unclear. Improvements in clinical symptoms, lesion characteristics and quality of life were observed for both genital and extragenital LS, with adverse events being tolerable.</p><p><strong>Conclusion: </strong>Single-arm trials with baricitinib and abrocitinib provide the highest current evidence for JAK inhibitors in treating genital LS. While evidence for extragenital LS remains limited to case reports, baricitinib shows therapeutic potential. These findings support baricitinib and abrocitinib as potential candidates for future randomized controlled trials.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656126","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":"Pharmacology and safety of TAS5315, a Bruton tyrosine kinase inhibitor, in healthy volunteers: First-in-human, randomized, ascending-dose studies.","authors":"Yuji Kumagai, Tomoe Fujita, Mika Maeda, Akiko Yamamoto, Hideki Amano","doi":"10.1002/bcp.70039","DOIUrl":"https://doi.org/10.1002/bcp.70039","url":null,"abstract":"<p><strong>Aim: </strong>TAS5315 is a Bruton tyrosine kinase (Btk) inhibitor in development for autoimmune and allergic diseases, including rheumatoid arthritis (RA) and chronic spontaneous urticaria (CSU). Two clinical studies evaluated the pharmacology and safety of single and multiple oral doses of TAS5315.</p><p><strong>Methods: </strong>Two phase 1 studies (single ascending-dose [SAD] and multiple ascending-dose [MAD]) assessed the pharmacokinetics (including effect of food), pharmacodynamics (Btk occupancy, inhibition of basophil activation) and safety of TAS5315 (up to 8 mg/day) in healthy males.</p><p><strong>Results: </strong>TAS5315 showed linear pharmacokinetics over a 0.01-8 mg dose range; maximum plasma concentration and area under the plasma concentration-time curve were reduced by ~40% by food. TAS5315 had dose dependent effects on Btk and basophil activation. In the SAD study, doses ≥2 mg resulted in mean Btk occupancy of almost 100% at 2 and 6 h, and >80% at 24 h, post-administration. TAS5315 1-8 mg/day inhibited basophil activation (mean change from baseline -55% to -89%). TAS5315 was generally tolerable. Although it dose-dependently reduced platelet aggregation (over 2-8 mg in both studies) and prolonged bleeding time (1-8 mg in the MAD study), no relationship between these effects and clinical symptoms was observed. All adverse drug reactions were mild and resolved without treatment; no noteworthy safety concerns were observed in either study.</p><p><strong>Conclusion: </strong>These data indicate TAS5315 has potential as a novel therapeutic for immunological diseases associated with aberrant Btk signalling, including RA and CSU. Further evaluation of TAS5315 is warranted.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633654","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":"Pharmacokinetics of betamethasone in pre-eclampsia: An in vivo and ex vivo study.","authors":"Sam Schoenmakers, Letao Li, Anna C M Kluivers, Michelle Broekhuizen, Madhavi S Harhangi, A H Jan Danser, Irwin Reiss, Karel Allegaert, Sjoerd A A van den Berg, Bertrand D van Zelst, Ron H N van Schaik, Philip L J DeKoninck, Emma Ronde, Sebastiaan D T Sassen, Sinno H P Simons, Birgit C P Koch","doi":"10.1002/bcp.70035","DOIUrl":"https://doi.org/10.1002/bcp.70035","url":null,"abstract":"<p><strong>Aims: </strong>To enhance understanding of betamethasone and its metabolites' pharmacokinetics in pregnancy, specifically early-onset pre-eclampsia, through a population pharmacokinetic model. Additionally, to investigate the placental metabolism and transfer of betamethasone and its main metabolites.</p><p><strong>Methods: </strong>A prospective, single-centre pharmacokinetic study was conducted in pregnant women (n = 28) with imminent preterm birth treated with intramuscular betamethasone. Betamethasone serum concentrations were determined from serial venous blood samples (n = 194). Placental transfer and metabolism were studied using ex vivo human placental perfusion (healthy term; n = 3) and placental explant experiments (healthy term, n = 4; early-onset pre-eclampsia, n = 4). Additionally, placental mRNA expression of CYP3A4, CYP3A7, 11β-hydroxysteroid dehydrogenase (HSD) 1 and 11β-HSD2 were quantified in healthy and early-onset pre-eclampsia placentas.</p><p><strong>Results: </strong>The population pharmacokinetic model was best described by a 2-compartment nonlinear mixed effects model. Betamethasone clearance in early-onset pre-eclamptic women was 60% lower of that observed in women without pre-eclampsia (9.35 vs. 15.78 L/h), resulting in a 40% median increase in maternal betamethasone exposure (1567 vs. 1114 ng h/mL). Ex vivo experiments showed placental transfer of betamethasone to the foetal circulation (foetal-to-maternal ratio 0.76 ± 0.05 [in a perfused placental cotyledon]). The placenta only converted betamethasone into 11-ketobetamethasone, with similar ratios in early-onset pre-eclampsia and healthy placental explants (3.0 ± 2.2 vs. 1.4 ± 0.4 per mg tissue, P = .27). The expression of 11β-HSD1 mRNA was lower in early-onset pre-eclampsia placentas (P = .015), while placental CYP3A7 and 11β-HSD2 mRNA expression were similar.</p><p><strong>Conclusion: </strong>Women with early-onset pre-eclampsia have elevated betamethasone exposure. Betamethasone transfers freely into the foetal circulation, with placental metabolism resulting only in 11-ketobetamethasone. Decreased placental 11β-HSD1 expression may play a role in increased betamethasone exposure in early-onset pre-eclampsia.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623667","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":"Factors influencing physicians' antimicrobial prescribing decisions: A systematic review of qualitative studies.","authors":"Savannah Reali, Yee Chin Kwang, Jin-Gun Cho, Jan-Willem Alffenaar, Parisa Aslani","doi":"10.1002/bcp.70011","DOIUrl":"https://doi.org/10.1002/bcp.70011","url":null,"abstract":"<p><p>Inappropriate and overuse of antimicrobials is increasing antimicrobial resistance. Understanding physicians' antimicrobial decision-making is essential for developing interventions to optimize prescribing. The aim of this review was to identify the factors that influence physicians' antimicrobial prescribing decisions. A systematic literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline and Scopus were searched from 2014 onwards using three key concepts: antimicrobial, prescribing and attitude. The search identified 11 038 articles for review. Studies were included if they used qualitative methods and obtained data directly from physicians. Factors influencing antimicrobial prescribing were extracted and categorized into physician-related, patient-related, medication- and condition-related, and external factors. A model of the antimicrobial prescribing process was created to illustrate how these factors influence decision-making. Fifty-three articles from 23 countries met the inclusion criteria. Forty factors influencing antimicrobial prescribing were identified, with the most common being time pressures, patient/carer demand for antimicrobials, diagnostic uncertainty, clinical experience, and the use of evidence-based guidelines and diagnostic tests. The harm to the patient and the physician of underprescribing were considered to outweigh the potential population harm of antimicrobial resistance due to overprescribing. Antimicrobial decision making is a complex process influenced by many different types of factors at each point in the prescribing journey. Awareness of these factors is vital for the success of interventions aiming to optimize antimicrobial prescribing. Future interventions should investigate how to balance individual and population harm whilst considering the individual factors that influence prescribing decisions.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603947","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":"Methotrexate toxicity and glucarpidase: A call for dose optimization.","authors":"Arjen Koppen, Maaike A Sikma, Frederike K Engels, Marise R Heerma van Voss, Martine E D Chamuleau, Imke H Bartelink, Marieke A Dijkman","doi":"10.1002/bcp.70044","DOIUrl":"https://doi.org/10.1002/bcp.70044","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603948","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-drug interaction study with itraconazole supplemented with physiologically based pharmacokinetic modelling to characterize the effect of CYP3A inhibitors on venglustat pharmacokinetics.","authors":"Li Li, Yan-Yan Zhang, Jyoti Sharma, Sylvaine Cartot-Cotton, Nigel Crawford, Sreeraj Macha, Yi Li, Jasminder Sahi","doi":"10.1002/bcp.70037","DOIUrl":"https://doi.org/10.1002/bcp.70037","url":null,"abstract":"<p><strong>Aims: </strong>Venglustat is an oral glucosylceramide synthase inhibitor under clinical investigation to treat various lysosomal storage diseases. Metabolism is a main pathway for its elimination in humans with CYP3A being the major contributor. This study aims to evaluate effect of CYP3A inhibition (using itraconazole) on venglustat exposure and to develop and validate a physiologically based pharmacokinetic (PBPK) model to assess effects of additional CYP3A inhibitors of varying potencies on venglustat pharmacokinetics.</p><p><strong>Methods: </strong>An open-label, single-sequence, 2-period drug-drug interaction (DDI) study was conducted in healthy subjects with coadministration of multiple twice daily oral doses of 100 mg itraconazole against a single dose of 15 mg venglustat. A minimal PBPK model was developed using available physicochemical, in vitro and in vivo pharmacokinetic data and validated using data from relevant venglustat clinical studies including the itraconazole DDI study. Effects of additional CYP3A inhibitors on venglustat exposure were predicted.</p><p><strong>Results: </strong>Coadministration with itraconazole increased venglustat area under the concentration-time curve by 2.03-fold (90% confidence interval [90%CI]: 1.81-2.27). Venglustat steady-state area under the concentration-time curve during a dosing interval following coadministration with strong (clarithromycin), moderate (fluconazole) and weak (fluvoxamine and cimetidine; with CYP2D6 inhibition turned off) CYP3A inhibitors is predicted to increase by 1.74- (5th-95th centile, 1.30-2.49), 1.52- (1.23-1.88), 1.08- (1.03-1.15) and 1.08-fold (1.04-1.12), respectively.</p><p><strong>Conclusion: </strong>The effect of itraconazole on venglustat exposure was quantified clinically, and a minimal PBPK model was successfully developed, validated and applied to assess DDI effect of additional CYP3A inhibitors on venglustat. The results help to further understand the DDI potential with venglustat and will inform dose recommendations with comedications.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603946","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":"Assessing GPT-4's accuracy in answering clinical pharmacological questions on pain therapy.","authors":"Anna Stroop, Tabea Stroop, Samer Zawy Alsofy, Moritz Wegner, Makoto Nakamura, Ralf Stroop","doi":"10.1002/bcp.70036","DOIUrl":"https://doi.org/10.1002/bcp.70036","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to evaluate the accuracy and completeness of GPT-4, a large language model, in answering clinical pharmacological questions related to pain therapy, with a focus on its potential as a tool for delivering patient-facing medical information. The objective was to assess its reliability in delivering medical information in the context of pain management.</p><p><strong>Methods: </strong>A cross-sectional survey-based study was conducted with healthcare professionals, including physicians and pharmacists. Participants submitted up to 8 clinical pharmacology questions on pain management, focusing on drug interactions, dosages and contraindications. GPT-4's responses were evaluated based on comprehensibility, detail, satisfaction, medical-pharmacological accuracy and completeness. Additionally, responses were compared to the German Drug Directory to assess their accuracy.</p><p><strong>Results: </strong>The majority of participants (99%) found GPT-4's responses comprehensible, while 84% considered the information detailed enough. Overall satisfaction was high, with 93% expressing satisfaction, and 96% deemed the responses medically accurate. However, only 63% rated the information as complete, with some identifying gaps in pharmacokinetics and drug interaction data. Usability was evaluated as good to excellent, with a System Usability Scale score of 83.38 (± 10.26).</p><p><strong>Conclusion: </strong>GPT-4 demonstrates potential as a tool for delivering medical information, particularly in pain management. However, limitations such as incomplete pharmacological data and the potential for contextual carryover in follow-up questions suggest that further refinement is necessary. Developing specialized artificial intelligence tools that integrate real-time pharmacological databases could improve accuracy and reliability for clinical decision-making.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596221","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":"Utilization and expenditure on medicines for the management of osteoporosis in Ireland: A repeated cross-sectional study.","authors":"Amelia Smith, Lisa Kelly, Claire Gorry, Bernard Duggan, Michael Barry","doi":"10.1002/bcp.70008","DOIUrl":"https://doi.org/10.1002/bcp.70008","url":null,"abstract":"<p><strong>Aim: </strong>Osteoporosis is a prevalent skeletal disease characterized by low bone mass and increased fracture risk. Management of osteoporosis typically involves antiresorptive and anabolic therapies, which are reimbursed in Ireland through various drug schemes. This study aims to summarize the utilization patterns associated with medicines used in the management of osteoporosis in Ireland.</p><p><strong>Methods: </strong>This study is a repeated cross-sectional analysis of the overall utilization of and expenditure on medicines used in the management of osteoporosis in Ireland. A number of additional drug utilization metrics are investigated: the rate of osteoporosis medication prescribing per 1000 General Medical Services eligible population, adherence to bisphosphonates, denosumab and teriparatide, and the proportion of patients initiating denosumab as first-line treatment.</p><p><strong>Results: </strong>There has been a significant change in the utilization of medicines used for the treatment of osteoporosis in Ireland over the last 13 years. The associated total annual expenditure was €28.7 million in 2011, increasing to €33.8 million in 2023. The most commonly used medicines have changed significantly over the period analysed; in 2011 the majority of patients were treated with bisphosphonates, whereas from 2019, the majority of patients were treated with denosumab. Poor patterns of treatment adherence were observed in this study.</p><p><strong>Conclusion: </strong>The findings suggest evolving patterns in osteoporosis management in the Irish context. The study highlights the need for ongoing monitoring of medication use to ensure safe, effective and cost-effective care in the context of an aging population at increasing risk for osteoporosis.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596232","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":"Anticoagulation intensity and outcomes among southeast-Asians with moderate-to-severe mitral valve stenosis.","authors":"Punyawee Puchsaka, Wipharak Rattanavipanon, Sararat Phetroong, Rudeekorn Ue-Sethasakdhi, Suparat Wattanasombat, Wattana Wongtheptien, Surakit Nathisuwan","doi":"10.1002/bcp.70034","DOIUrl":"https://doi.org/10.1002/bcp.70034","url":null,"abstract":"<p><strong>Objective: </strong>To determine the optimal anticoagulation intensity of warfarin in a South-East Asian population with moderate-to-severe rheumatic mitral stenosis.</p><p><strong>Methods: </strong>A multicentre, retrospective study examined patients with rheumatic mitral stenosis who had not undergone valve replacement or repair and required long-term warfarin therapy at two hospitals in Thailand from 2013 to 2018. The main outcomes were thromboembolism and major bleeding. Incidence rate ratios for these events at each level of anticoagulation intensity (international normalized ratio [INR]) were compared.</p><p><strong>Results: </strong>The study included 933 patients with 3538 patient-years of follow-up, a mean follow-up of 3.8 years and 23 700 INR values. Mean age was 56.1 ± 11.8 years. During follow-up, there were 149 thromboembolic events (4.2 per 100 patient-years) and 132 major bleeding events (3.7 per 100 patient-years). Net adverse clinical events were lowest at INR 2.50-2.99, with no significant difference between INR 2.00-2.49 and 3.00-3.50. Standard INR (2.0-3.0) and high-intensity INR (2.5-3.5) had comparable net adverse clinical event rates (incidence rate ratio 0.99, 95% confidence interval [CI] 0.66-1.54, P = .99). However, thromboembolism incidence was higher with standard INR (incidence rate ratio 2.49, 95% CI 1.13-6.23, P = .013), while major bleeding was lower (incidence rate ratio 0.57, 95% CI 0.35-0.98, P = .045). No significant difference in intracranial haemorrhage rates was observed between the two INR intensities.</p><p><strong>Conclusion: </strong>The standard anticoagulation intensity is an optimal range for Asian population with moderate-to-severe rheumatic mitral stenosis. High intensity anticoagulation (INR of 2.50-3.50) further reduces thromboembolism but increases major bleeding but not intracranial haemorrhage.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596159","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-tumour growth inhibition modelling of brigimadlin using phase I solid tumour data to support phase II dose selection.","authors":"Ida Neldemo, Kamunkhwala Gausi, Céline Sarr, Lena E Friberg, Reinhard Sailer, Mehdi Lahmar, Girish Jayadeva, Alejandro Pérez-Pitarch, Ulrike Schmid, David Busse","doi":"10.1002/bcp.70031","DOIUrl":"https://doi.org/10.1002/bcp.70031","url":null,"abstract":"<p><strong>Aims: </strong>Brigimadlin (BI 907828) is a potent, oral MDM2-p53 antagonist under clinical investigation for the treatment of advanced solid tumours. A brigimadlin exposure-tumour growth inhibition (E-TGI) model was developed to support the recommended phase II dose (RP2D) selection of brigimadlin in future clinical trials.</p><p><strong>Methods: </strong>Population modelling was applied to analyse longitudinal tumour size (sum of longest diameters, SLD) data of 151 patients from a phase I trial treated with 5-80 mg brigimadlin every third or fourth week (q3w/q4w). The impact of brigimadlin exposure on tumour shrinkage was assessed and the effects of patient- and tumour-related covariates on model parameters were explored. The final E-TGI model was used to simulate the effect of brigimadlin treatment on longitudinal SLD. The probability of dropout from tumour assessments were characterized via logistic regression and included in simulations to allow for realistic predictions of tumour shrinkage over time.</p><p><strong>Results: </strong>The E-TGI model adequately characterized the observed SLD data over time. Simulations demonstrated a substantially stronger tumour shrinkage with higher dose, based on the identified exposure-response relationship. For patients with the most common tumour (dedifferentiated liposarcoma) and standard body weight (70 kg) and remaining in the study for 1 year, the median relative change from baseline in tumour size was 0.141%, -4.48%, -10.8% and -17.4%, for treatment with 20, 30, 45 and 60 mg brigimadlin q3w doses, respectively.</p><p><strong>Conclusions: </strong>The developed E-TGI model predicted that higher doses of brigimadlin resulted in a substantially stronger tumour shrinkage. These results contributed to selecting 45 mg brigimadlin q3w dose as RP2D in subsequent clinical trials.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596226","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}