glp - 1ra诱导的胃肠运动延迟:PBPK分析对共给药药物吸收的预测影响。

IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Pharmacotherapy Pub Date : 2025-02-23 DOI:10.1002/phar.70007
Levi Hooper, Shuhan Liu, Manjunath P Pai
{"title":"glp - 1ra诱导的胃肠运动延迟:PBPK分析对共给药药物吸收的预测影响。","authors":"Levi Hooper, Shuhan Liu, Manjunath P Pai","doi":"10.1002/phar.70007","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are breakthrough medicines for obesity treatment and have rapidly gained widespread clinical application. Although GLP-1RAs are generally not associated with drug-drug interactions (DDIs) via drug metabolism or transporter pathways, their effects on reduced gastrointestinal (GI) motility could influence the pharmacokinetics of coadministered oral medications.</p><p><strong>Objectives: </strong>This study uses physiologically based pharmacokinetic (PBPK) modeling to evaluate the DDI potential of GLP-1RA-induced GI motility delays.</p><p><strong>Methods: </strong>Using Certara's Simcyp™ Simulator V23, we modeled the pharmacokinetics of atorvastatin, metformin, metoprolol, ethinyl estradiol, and digoxin in a virtual cohort of obese adults (n = 1000). GLP-1RA-related gastric emptying delays were simulated based on capsule endoscopy data from liraglutide-treated patients. Results were compared with clinical data from semaglutide and liraglutide users. Additionally, exploratory analyses were conducted on frequently coadministered drugs identified from the 2022 Medical Expenditure Panel Survey, including rosuvastatin and dabigatran.</p><p><strong>Results: </strong>GLP-1RA-induced gastric emptying delays led to increased area under the concentration-time curve (AUC) and prolonged time to maximum concentration (Tmax) for several medications. The model outputs for rosuvastatin, valsartan, and dabigatran indicate increases in AUC by 64%, 90%, and 205%, respectively. Dabigatran, a narrow therapeutic index anticoagulant, exhibited the most significant changes, raising potential concerns of higher drug exposure.</p><p><strong>Conclusions: </strong>PBPK modeling suggests that GLP-1RAs can influence the pharmacokinetics of oral medications by delaying gastric emptying, potentially leading to clinically relevant DDIs. While further clinical validation and pharmacovigilance is needed, these findings highlight the importance of PBPK tools in predicting and potentially mitigating risks associated with GLP-1RA use.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":" ","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"GLP-1RA-induced delays in gastrointestinal motility: Predicted effects on coadministered drug absorption by PBPK analysis.\",\"authors\":\"Levi Hooper, Shuhan Liu, Manjunath P Pai\",\"doi\":\"10.1002/phar.70007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are breakthrough medicines for obesity treatment and have rapidly gained widespread clinical application. Although GLP-1RAs are generally not associated with drug-drug interactions (DDIs) via drug metabolism or transporter pathways, their effects on reduced gastrointestinal (GI) motility could influence the pharmacokinetics of coadministered oral medications.</p><p><strong>Objectives: </strong>This study uses physiologically based pharmacokinetic (PBPK) modeling to evaluate the DDI potential of GLP-1RA-induced GI motility delays.</p><p><strong>Methods: </strong>Using Certara's Simcyp™ Simulator V23, we modeled the pharmacokinetics of atorvastatin, metformin, metoprolol, ethinyl estradiol, and digoxin in a virtual cohort of obese adults (n = 1000). GLP-1RA-related gastric emptying delays were simulated based on capsule endoscopy data from liraglutide-treated patients. Results were compared with clinical data from semaglutide and liraglutide users. Additionally, exploratory analyses were conducted on frequently coadministered drugs identified from the 2022 Medical Expenditure Panel Survey, including rosuvastatin and dabigatran.</p><p><strong>Results: </strong>GLP-1RA-induced gastric emptying delays led to increased area under the concentration-time curve (AUC) and prolonged time to maximum concentration (Tmax) for several medications. The model outputs for rosuvastatin, valsartan, and dabigatran indicate increases in AUC by 64%, 90%, and 205%, respectively. Dabigatran, a narrow therapeutic index anticoagulant, exhibited the most significant changes, raising potential concerns of higher drug exposure.</p><p><strong>Conclusions: </strong>PBPK modeling suggests that GLP-1RAs can influence the pharmacokinetics of oral medications by delaying gastric emptying, potentially leading to clinically relevant DDIs. While further clinical validation and pharmacovigilance is needed, these findings highlight the importance of PBPK tools in predicting and potentially mitigating risks associated with GLP-1RA use.</p>\",\"PeriodicalId\":20013,\"journal\":{\"name\":\"Pharmacotherapy\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2025-02-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmacotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/phar.70007\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/phar.70007","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

背景:胰高血糖素样肽-1受体激动剂(Glucagon-like peptide-1 receptor agonists, GLP-1RAs)是治疗肥胖的突破性药物,已迅速获得广泛的临床应用。虽然GLP-1RAs通常不通过药物代谢或转运途径与药物-药物相互作用(ddi)相关,但它们对降低胃肠道(GI)运动的影响可能会影响共给口服药物的药代动力学。目的:本研究采用基于生理的药代动力学(PBPK)模型来评估glp - 1ra诱导的GI运动延迟的DDI潜力。方法:使用Certara的Simcyp™模拟器V23,我们模拟了阿托伐他汀、二甲双胍、美托洛尔、炔雌醇和地高辛在虚拟肥胖成人队列中的药代动力学(n = 1000)。根据利拉鲁肽治疗患者的胶囊内窥镜数据模拟glp - 1ra相关的胃排空延迟。结果比较了西马鲁肽和利拉鲁肽使用者的临床数据。此外,对2022年医疗支出小组调查中确定的常用共同用药进行了探索性分析,包括瑞舒伐他汀和达比加群。结果:glp - 1ra诱导的胃排空延迟导致几种药物的浓度-时间曲线下面积(AUC)增加,达到最大浓度(Tmax)的时间延长。瑞舒伐他汀、缬沙坦和达比加群的模型输出显示AUC分别增加了64%、90%和205%。达比加群,一种窄治疗指数抗凝剂,表现出最显著的变化,引起了对更高药物暴露的潜在担忧。结论:PBPK模型提示GLP-1RAs通过延迟胃排空影响口服药物的药代动力学,可能导致临床相关的ddi。虽然需要进一步的临床验证和药物警戒,但这些发现强调了PBPK工具在预测和潜在地减轻GLP-1RA使用相关风险方面的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
GLP-1RA-induced delays in gastrointestinal motility: Predicted effects on coadministered drug absorption by PBPK analysis.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are breakthrough medicines for obesity treatment and have rapidly gained widespread clinical application. Although GLP-1RAs are generally not associated with drug-drug interactions (DDIs) via drug metabolism or transporter pathways, their effects on reduced gastrointestinal (GI) motility could influence the pharmacokinetics of coadministered oral medications.

Objectives: This study uses physiologically based pharmacokinetic (PBPK) modeling to evaluate the DDI potential of GLP-1RA-induced GI motility delays.

Methods: Using Certara's Simcyp™ Simulator V23, we modeled the pharmacokinetics of atorvastatin, metformin, metoprolol, ethinyl estradiol, and digoxin in a virtual cohort of obese adults (n = 1000). GLP-1RA-related gastric emptying delays were simulated based on capsule endoscopy data from liraglutide-treated patients. Results were compared with clinical data from semaglutide and liraglutide users. Additionally, exploratory analyses were conducted on frequently coadministered drugs identified from the 2022 Medical Expenditure Panel Survey, including rosuvastatin and dabigatran.

Results: GLP-1RA-induced gastric emptying delays led to increased area under the concentration-time curve (AUC) and prolonged time to maximum concentration (Tmax) for several medications. The model outputs for rosuvastatin, valsartan, and dabigatran indicate increases in AUC by 64%, 90%, and 205%, respectively. Dabigatran, a narrow therapeutic index anticoagulant, exhibited the most significant changes, raising potential concerns of higher drug exposure.

Conclusions: PBPK modeling suggests that GLP-1RAs can influence the pharmacokinetics of oral medications by delaying gastric emptying, potentially leading to clinically relevant DDIs. While further clinical validation and pharmacovigilance is needed, these findings highlight the importance of PBPK tools in predicting and potentially mitigating risks associated with GLP-1RA use.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Pharmacotherapy
Pharmacotherapy 医学-药学
CiteScore
7.80
自引率
2.40%
发文量
93
审稿时长
4-8 weeks
期刊介绍: Pharmacotherapy is devoted to publication of original research articles on all aspects of human pharmacology and review articles on drugs and drug therapy. The Editors and Editorial Board invite original research reports on pharmacokinetic, bioavailability, and drug interaction studies, clinical trials, investigations of specific pharmacological properties of drugs, and related topics.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信