British journal of clinical pharmacology最新文献_第6页

Population pharmacokinetic analysis of the interaction of digoxin with N-desethylamiodarone in patients with atrial fibrillation and heart failure. 地高辛与n -去乙基胺碘酮在房颤心衰患者中相互作用的人群药动学分析。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-27 DOI: 10.1002/bcp.70075

Toshinori Hirai, Hidefumi Kasai, Tsuyoshi Shiga

{"title":"Population pharmacokinetic analysis of the interaction of digoxin with N-desethylamiodarone in patients with atrial fibrillation and heart failure.","authors":"Toshinori Hirai, Hidefumi Kasai, Tsuyoshi Shiga","doi":"10.1002/bcp.70075","DOIUrl":"https://doi.org/10.1002/bcp.70075","url":null,"abstract":"Aims: To evaluate the effects of amiodarone and/or N-desethylamiodarone concentrations on digoxin pharmacokinetics and determine the optimal dose of digoxin combined with amiodarone in Japanese patients with atrial fibrillation and heart failure.Methods: A population pharmacokinetic analysis of 3288 points from 368 patients receiving oral digoxin, including 48 (13%) who were coadministered amiodarone, was performed. A 1-compartment model with first-order absorption with amiodarone or N-desethylamiodarone as time-varying covariates for apparent digoxin clearance was constructed using stepwise forward inclusion and backward elimination approaches. The percentage of patients with digoxin values in the toxic range (≥0.9 ng/mL) was evaluated with Monte Carlo simulation.Results: The median serum digoxin concentration was 0.75 ng/mL; the median plasma concentrations of amiodarone and N-desethylamiodarone were 610 and 644 ng/mL, respectively. The final model for oral clearance of digoxin was explained by creatinine clearance (CLcr) and the N-desethylamiodarone concentration. Digoxin clearance increased by 21% when CLcr was doubled and decreased by 3% when the N-desethylamiodarone concentration increased by 100 ng/mL. In the simulation, the proportion of patients with values in the toxic range was high at 0.125 mg daily among patients taking amiodarone. A daily dose of 0.0625 mg is recommended for patients with a CLcr >30 mL/min. For patients with a CLcr ≤30 mL/min and an N-desethylamiodarone concentration >600 ng/mL, a daily dose of 0.03125 mg is recommended because of reduced digoxin clearance.Conclusions: This study revealed that renal impairment and high plasma N-desethylamiodarone concentrations reduce digoxin clearance in patients with atrial fibrillation and heart failure.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966237","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}

引用次数: 0

A novel approach for first-in-human dose selection using population dose-response modelling to find a minimum anticipated biological effect level. 一种利用群体剂量反应模型寻找最小预期生物效应水平的首次人体剂量选择的新方法。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-27 DOI: 10.1002/bcp.70067

Lin Yuan, Meghana Kulkarni, Evan Chiswick, Cheryl Koh, Peter Sandy, Salah Nabhan, Woody Sherman, Melissa Johnson, Judy Wang, Gerald Falchook, Jennifer Johnson, Christopher Winter, Humphrey Gardner, Arijit Chakravarty, Madison Stoddard

{"title":"A novel approach for first-in-human dose selection using population dose-response modelling to find a minimum anticipated biological effect level.","authors":"Lin Yuan, Meghana Kulkarni, Evan Chiswick, Cheryl Koh, Peter Sandy, Salah Nabhan, Woody Sherman, Melissa Johnson, Judy Wang, Gerald Falchook, Jennifer Johnson, Christopher Winter, Humphrey Gardner, Arijit Chakravarty, Madison Stoddard","doi":"10.1002/bcp.70067","DOIUrl":"https://doi.org/10.1002/bcp.70067","url":null,"abstract":"Aims: Choice of first-in-human dose has critical implications for the safety of Phase I participants as well as the likelihood of reaching the therapeutic dose range during escalation. In this analysis, we present a population concentration-response modelling approach for selecting the Phase I starting dose for a novel stimulator of interferon response cGAMP interactor 1 (STING) agonist, SNX281.Methods: Given the immune agonist mechanism of SNX281, we opted to select the starting dose according to the minimum anticipated biological effect level (MABEL). To determine the MABEL concentration, we fitted a population concentration-response model to cytokine induction data from an ex vivo whole blood assay. We selected a whole blood assay to obviate the need for free fraction scaling for this highly protein-bound drug. We used the population concentration-response model to estimate the lower 10th percentile for the 10% maximal interferon-β response concentration of SNX281, which was chosen as the MABEL concentration. We translated the ex vivo MABEL concentration to a human MABEL dose using a human pharmacokinetic projection based on allometric scaling from preclinical species.Results: The human dose-peak concentration relationship projection fell within 2-fold of the clinical result. After the application of a safety factor, the MABEL dose was applied in the clinic and did not demonstrate dose-limiting toxicities.Conclusions: Our novel population modelling-based MABEL strategy for first-in-human dose selection resulted in successful clinical translation of a small molecule STING agonist.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959298","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}

引用次数: 0

Spotlight commentary: De-labelling the truth: Clearing the fog around antibiotic allergy labels. 焦点评论：去标签真相：清除抗生素过敏标签周围的迷雾。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-27 DOI: 10.1002/bcp.70085

Iva Mikulić, Robert Likić

引用次数: 0

A phase 1, randomized, crossover trial to assess the effect of itraconazole on the pharmacokinetics of dordaviprone in healthy adults. 一项评估伊曲康唑对健康成人多达维易感药代动力学影响的1期随机交叉试验。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-27 DOI: 10.1002/bcp.70080

Shamia L Faison, Joelle Batonga, Thangam Arumugham, Angela Bartkus, Marion E Morrison, Mark J Mullin, Tim Tippin, Odin Naderer

{"title":"A phase 1, randomized, crossover trial to assess the effect of itraconazole on the pharmacokinetics of dordaviprone in healthy adults.","authors":"Shamia L Faison, Joelle Batonga, Thangam Arumugham, Angela Bartkus, Marion E Morrison, Mark J Mullin, Tim Tippin, Odin Naderer","doi":"10.1002/bcp.70080","DOIUrl":"https://doi.org/10.1002/bcp.70080","url":null,"abstract":"Aims: Dordaviprone (ONC201) is a novel, small molecule with antitumor efficacy in gliomas. The aim of this work was to evaluate the pharmacokinetics and safety of dordaviprone when given alone and when coadministered with a strong cytochrome P450 (CYP)3A4 inhibitor, itraconazole.Methods: In vitro human liver microsomes and recombinant human CYP enzyme assays were used to assess CYP-mediated metabolism of dordaviprone. The clinical study was conducted in 18 healthy male and female participants as part of a larger 3 period open-label, randomized, crossover bioequivalence and drug-drug interaction evaluation. Dordaviprone and metabolite ONC207 plasma concentrations were determined by validated liquid chromatography-tandem mass spectrometry methods.Results: In vitro assessments of CYP-mediated dordaviprone metabolism indicated that CYP3A4 was the major CYP involved in the oxidation of dordaviprone. Accordingly, concomitant administration of dordaviprone with itraconazole significantly increased dordaviprone plasma maximum plasma concentration and area under the plasma concentration-time curve by 1.9 and 4.5-fold, respectively, compared to dordaviprone alone. Treatment-emergent adverse events were reported by 1 (5.6%) participant after receiving dordaviprone alone, and by 4 (22.2%) participants after receiving dordaviprone with itraconazole.Conclusion: Concomitant administration of dordaviprone with itraconazole significantly increased dordaviprone exposure confirming CYP3A4 is a major clearance pathway for dordaviprone. While dordaviprone was generally well tolerated when administered as a single 125-mg dose with concomitant itraconazole, dose adjustment in patients receiving 625 mg dordaviprone with strong CYP3A4 inhibitors is warranted.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976704","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}

引用次数: 0

Assessment of individual disciplines before and after a shift to an active-learning and integrated curriculum. 在向主动学习和综合课程转变之前和之后对个别学科进行评估。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-27 DOI: 10.1002/bcp.70076

Ivy Click, Nicole H Lewis, Kelly Karpa

{"title":"Assessment of individual disciplines before and after a shift to an active-learning and integrated curriculum.","authors":"Ivy Click, Nicole H Lewis, Kelly Karpa","doi":"10.1002/bcp.70076","DOIUrl":"https://doi.org/10.1002/bcp.70076","url":null,"abstract":"Aims: Curricular revisions that replace classroom lectures with student-led, self-directed learning are difficult for faculty and students due to fear of change and the unknown. The study aimed to compare student performance on standardized assessments across the transition from a traditional, discipline-based curriculum to an active-learning, integrated curriculum.Methods: Using a database of faculty-generated questions, we used Welch's 2 sample t-tests and the Wilcoxon rank sum test to compare student performance in basic science disciplines before and after a curriculum renewal. Additionally, to investigate student outcomes on standardized assessments before and after the curricular transition, we used independent t-tests to compare results from the Comprehensive Basic Science Exam and simple differences between groups to evaluate performance on the US Medical Licensing Exam Step 1.Results: Overall results from the question database as well as standardized test performance confirm that students performed the same or better in the new curriculum compared to past performance in the legacy curriculum as well as when compared to peers nationally. In some disciplines, students demonstrated improved performance. Of students who experienced the new curriculum, 8% more performed at or above the national comparison group on pharmacology-related questions than the legacy curriculum students.Conclusions: We believe our curricular structure as well as our approach to tracking student performance could be a model for other health professions that are considering curricular transformation.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970898","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}

引用次数: 0

Influence of anticoagulant concomitant medication on wound healing: Analysis of a multicentre cohort of 212 patients with a uniform wound model. 抗凝剂联合用药对伤口愈合的影响：一项212例统一伤口模型患者的多中心队列分析

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-27 DOI: 10.1002/bcp.70073

Christian Seebauer, Fares Hanafieh, Jan Wolff, Hans-Robert Metelmann, Marcus Vollmer

{"title":"Influence of anticoagulant concomitant medication on wound healing: Analysis of a multicentre cohort of 212 patients with a uniform wound model.","authors":"Christian Seebauer, Fares Hanafieh, Jan Wolff, Hans-Robert Metelmann, Marcus Vollmer","doi":"10.1002/bcp.70073","DOIUrl":"https://doi.org/10.1002/bcp.70073","url":null,"abstract":"Aims: Various factors can impair wound healing by disrupting key stages of the process. This study evaluates the impact of concomitant anticoagulant medication on wound healing in a cohort of 212 patients.Methods: Data from 2 open-label, blindly evaluated, prospective, randomized, multicentre phase III trials (n = 212) were analysed. Healing durations of patients taking anticoagulants were compared to a control group (split-thickness skin graft donor site halves treated with standard moist wound dressing). Kaplan-Meier estimators and multivariable Cox regression were applied.Results: Kaplan-Meier analysis demonstrated significantly accelerated wound healing in patients treated with enoxaparin or nadroparin. Among monotherapies, 75% of patients on enoxaparin achieved wound closure within 16.5 days (95% confidence interval [CI]: 14-21), and those on nadroparin within 15 days (95% CI: 11.5-19), compared to 24 days (95% CI: 20-28) in patients receiving other anticoagulants (log-rank test: P < .001). Cox regression confirmed a significantly faster healing rate with enoxaparin or nadroparin (hazard ratio = 1.50, 95% CI: 1.02-2.19, P = .039).Conclusion: Enoxaparin and nadroparin may enhance wound healing, whereas phenprocoumon, acetylsalicylic acid, and certain low-molecular-weight heparins (certoparin, tinzaparin, dalteparin, bemiparin) appear to delay wound healing. Anticoagulant monotherapy with enoxaparin or nadroparin should be considered postoperatively when feasible.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975754","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}

引用次数: 0

The feasibility of pharmacokinetic-based dosing of hydroxyurea for children with sickle cell anaemia in Uganda: Baseline results of the alternative dosing and prevention of transfusions trial. 基于药代动力学的羟脲给药治疗乌干达镰状细胞贫血儿童的可行性：替代给药和预防输血试验的基线结果。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-13 DOI: 10.1002/bcp.70071

Alexandra Power-Hays, Ruth Namazzi, Min Dong, Caroline Kazinga, Charles Kato, Sadat Aliwuya, Kathryn McElhinney, Andrea L Conroy, Adam Lane, Chandy John, Alexander A Vinks, Teresa Latham, Robert O Opoka, Russell E Ware

{"title":"The feasibility of pharmacokinetic-based dosing of hydroxyurea for children with sickle cell anaemia in Uganda: Baseline results of the alternative dosing and prevention of transfusions trial.","authors":"Alexandra Power-Hays, Ruth Namazzi, Min Dong, Caroline Kazinga, Charles Kato, Sadat Aliwuya, Kathryn McElhinney, Andrea L Conroy, Adam Lane, Chandy John, Alexander A Vinks, Teresa Latham, Robert O Opoka, Russell E Ware","doi":"10.1002/bcp.70071","DOIUrl":"https://doi.org/10.1002/bcp.70071","url":null,"abstract":"Pharmacokinetic (PK)-guided dosing of hydroxyurea for children with sickle cell anaemia (SCA) could optimize dosing and improve outcomes, but its feasibility has not been demonstrated in low-resource settings where the majority of affected children live. Alternative Dosing And Prevention of Transfusions (ADAPT) is a prospective trial evaluating blood transfusions and the feasibility of determining PK-guided, hydroxyurea maximum tolerated doses (MTD) for children with SCA in Uganda, using portable high-performance liquid chromatography (HPLC) and a novel PK software programme (HdxSim). ADAPT enrolled 106 participants, and 100% completed PK testing. PK-guided doses were generated for 78%, of which 38% were within the protocol-defined range. Accurately, measuring serum hydroxyurea concentrations via HPLC and the potential for hydroxyurea degradation impacted the feasibility. Ensuring that people with SCA globally have access to hydroxyurea is imperative, and improving treatment strategies requires ongoing innovation including PK-guided dosing. ADAPT is registered at ClinicalTrials.gov (NCT05662098).","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980785","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}

引用次数: 0

Trends in gabapentinoid prescribing: A nationwide Danish drug utilization study. 加巴喷丁类药物处方趋势：丹麦全国药物使用研究。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-09 DOI: 10.1002/bcp.70060

Anton Pottegård, Lotte Rasmussen, Morten Olesen, Anne Mette Skov Sørensen, Zandra Nymand Ennis, Joseph Kane, Sarah Baxter, Blánaid Hicks

{"title":"Trends in gabapentinoid prescribing: A nationwide Danish drug utilization study.","authors":"Anton Pottegård, Lotte Rasmussen, Morten Olesen, Anne Mette Skov Sørensen, Zandra Nymand Ennis, Joseph Kane, Sarah Baxter, Blánaid Hicks","doi":"10.1002/bcp.70060","DOIUrl":"https://doi.org/10.1002/bcp.70060","url":null,"abstract":"Aims: Pregabalin and gabapentin are increasingly used for pain and other conditions. Concerns exist about overuse as well as potential misuse and abuse. To guide rational prescribing practices, we provide detailed nationwide data on the use of gabapentinoids in Denmark.Methods: We conducted a nationwide descriptive drug utilization study using the Danish healthcare registries to describe the use of gabapentinoids among Danish adults 2010-2023. We described overall use patterns, temporal trends, user characteristics, skewness of use, treatment duration and concomitant medication use.Results: The prevalence of gabapentinoid use increased almost four-fold from 11 per 1000 adults in 2010 to 41 in 2023 with the highest use among individuals aged 80+ years (96 per 1000 in 2023). Gabapentin and pregabalin were used equally. The median age of users increased from 58 years in 2010 to 63 years in 2023, while a decline was observed in the proportion with concomitant use of other drug classes, including benzodiazepines or opioids. Only 7% of patients were continuously treated for 3 years following initiation, while 22% were currently treated after 3 years (allowing treatment breaks). The use of gabapentinoids were somewhat skewed with 1% of users accounting for 7.3% of use in 2023.Conclusion: The use of gabapentinoids has increased dramatically in recent years, in particular, among the elderly, and adherence was low. Increased attention to the increasing use of gabapentinoids is warranted to ensure rational use of this drug class.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970901","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}

引用次数: 0

Analysis of 4616 clinical trial initial submissions received by the Medicines and Healthcare products Regulatory Agency between February 2019 and October 2023. 对2019年2月至2023年10月期间药品和保健产品监管机构收到的4616份临床试验初步提交的分析。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-09 DOI: 10.1002/bcp.70061

Andrea Manfrin, Kingyin Lee, James Pound, Munir Pirmohamed, June Raine

{"title":"Analysis of 4616 clinical trial initial submissions received by the Medicines and Healthcare products Regulatory Agency between February 2019 and October 2023.","authors":"Andrea Manfrin, Kingyin Lee, James Pound, Munir Pirmohamed, June Raine","doi":"10.1002/bcp.70061","DOIUrl":"https://doi.org/10.1002/bcp.70061","url":null,"abstract":"Aims: This study aimed to analyse clinical trial initial submissions received by the MHRA between February 2019 and October 2023.Methods: Data on submissions were extracted from the clinical trials unit data bank. The primary end-point was the type of clinical trial initial submissions. Secondary end-points were sponsor types, participant demographics, healthy volunteers, health categories and studies involving first in human and advanced therapy medicinal products. The analysis used descriptive statistics for all categorical variables.Results: MHRA received 4616 submissions. The highest percentage was in 2020 (22.8%) and the lowest in 2023 (17.2%). Phase 3 submissions were the highest (32.6%) and and phase 4 the lowest (5.2%). Commercial sponsors represented 85.1% of the total submissions. Both sexes were included in most trials (90%), while the number of submissions involving females only (3.7%) was lower than male only trials (6.1%). The elderly population was represented in 67.7% of trials with pregnant and breastfeeding women represented in 1.1% and 0.6% of trials, respectively. Breastfeeding women were not included in phase 1. Paediatric trials mostly involved adolescents. Healthy volunteers were included in 16.5% of the total submissions. The most common health category was cancer (29.4%), with the lowest being pain. First in human submissions represented 12.7% and advanced therapy medicinal products 3.4% of submissions.Conclusions: These results highlight the clinical trial landscape in the United Kingdom and represent an important baseline for policymakers, healthcare providers, sponsors and patients and will enable an assessment of how policy changes can improve the variety and number of clinical trials.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965075","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}

引用次数: 0

Pharmacokinetics, pharmacodynamics and safety profile of SKB336, a selective inhibitor of coagulation factor XI/XIa in healthy subjects. 凝血因子XI/XIa选择性抑制剂SKB336在健康人体内的药代动力学、药效学和安全性

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2025-04-09 DOI: 10.1002/bcp.70043

Qian Xiang, Zhiyan Liu, Qiufen Xie, Nan Zhao, Shuang Zhou, Linyu Cao, Xia Zhao, Yaling Li, Jing Si, Qingmei Wu, Junyou Ge, Yimin Cui

{"title":"Pharmacokinetics, pharmacodynamics and safety profile of SKB336, a selective inhibitor of coagulation factor XI/XIa in healthy subjects.","authors":"Qian Xiang, Zhiyan Liu, Qiufen Xie, Nan Zhao, Shuang Zhou, Linyu Cao, Xia Zhao, Yaling Li, Jing Si, Qingmei Wu, Junyou Ge, Yimin Cui","doi":"10.1002/bcp.70043","DOIUrl":"https://doi.org/10.1002/bcp.70043","url":null,"abstract":"Aims: Coagulation factor XI (FXI) plays a crucial role in the intrinsic coagulation pathway, and inhibitors targeting it may mitigate the risk of haemorrhage compared to anticoagulants currently on the market. SKB336, a novel selective inhibitor of FXI/FXIa, has been shown to prolong the activated partial thromboplastin time (APTT) in both in vitro and in vivo studies. This study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of SKB336 in healthy subjects.Methods: In this randomized, single-blinded, placebo-controlled and dose-escalation first-in-human phase I study, 60 healthy subjects were allocated to 6 cohorts (0.1, 0.3, 0.6, 1.25, 2.5 and 4 mg/kg) and received a single subcutaneous injection of SKB336 or placebo in a 4:1 ratio. The safety, tolerability, pharmacokinetics and immunogenicity were measured up to 85 days postdose. Exploratory analysis consisted of FXI activity and APTT.Results: SKB336 was well tolerated in all 6 cohorts, without any haemorrhagic events, reported deaths or serious adverse events. No significant dose-dependent correlation was observed with the incidence of adverse events. Dose-dependent increases in the maximum observed drug concentration and area under the plasma concentration-time curve were observed. The mean elimination half-life was 21.3-33.5 days, indicating a potential monthly dosing frequency. The maximum inhibition rate of FXI activity for all 6 cohorts reached 0, 17, 28, 48, 54 and 59%, respectively. The maximum APTT ratio to baseline reached 1.09-, 1.26-, 1.47-, 1.77, 1.91- and 2.00-fold, respectively.Conclusion: SKB336 was generally tolerated, without any bleeding events in healthy volunteers. Besides, SKB336 presented a persistent dose-dependent prolongation of APTT and duration of FXI inhibition.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966299","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}

引用次数: 0