Evaluation of Complex Drug Interactions Between Elexacaftor-Tezacaftor-Ivacaftor and Statins Using Physiologically Based Pharmacokinetic Modeling.

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Eunjin Hong, Peter S Chung, Adupa P Rao, Paul M Beringer
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引用次数: 0

Abstract

Background/Objectives: The increasing use of statins in people with cystic fibrosis (CF) necessitates the investigation of potential drug-drug interactions (DDI) of statins with cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor, tezacaftor, and ivacaftor (ETI). The interactions may involve the potential inhibition of cytochrome P450 isoenzymes (CYPs), organic anion-transporting polypeptides (OATPs), and Breast Cancer Resistance Protein (BCRP) by ETI. This presents a therapeutic challenge in CF due to the potential for elevated statin levels, consequently heightening the risk of myopathy. This study aimed to predict potential DDIs between statins and ETI using a physiologically based pharmacokinetic (PBPK) modeling approach. Methods: We performed in vitro assays to measure the inhibitory potency of ETI against OATPs and CYP2C9 and incorporated these data into our PBPK models alongside published inhibitory parameters for BCRP and CYP3A4. Results: The PBPK simulation showed that atorvastatin had the highest predicted AUC ratio (3.27), followed by pravastatin (2.27), pitavastatin (2.24), and rosuvastatin (1.83). Conclusions: Based on these findings, rosuvastatin appears to exhibit a weak interaction with ETI, whereas other statins exhibited a moderate interaction, potentially requiring appropriate dose reductions. These data indicate potential clinically significant DDIs between ETI and certain statins, which warrants a clinical study to validate these findings.

利用基于生理的药代动力学模型评估Elexacaftor-Tezacaftor-Ivacaftor与他汀类药物之间的复杂药物相互作用。
背景/目的:囊性纤维化(CF)患者越来越多地使用他汀类药物,有必要研究他汀类药物与囊性纤维化跨膜传导调节剂(CFTR)的潜在药物-药物相互作用(DDI),包括elexaftor、tezacaftor和ivacaftor (ETI)。这种相互作用可能涉及ETI对细胞色素P450同工酶(CYPs)、有机阴离子转运多肽(OATPs)和乳腺癌抵抗蛋白(BCRP)的潜在抑制。这给CF的治疗带来了挑战,因为他汀类药物水平可能升高,从而增加了肌病的风险。本研究旨在使用基于生理的药代动力学(PBPK)建模方法预测他汀类药物和ETI之间潜在的ddi。方法:我们进行了体外实验,测量ETI对ooatp和CYP2C9的抑制能力,并将这些数据与已发表的BCRP和CYP3A4的抑制参数一起纳入我们的PBPK模型。结果:PBPK模拟显示,阿托伐他汀的AUC预测值最高(3.27),其次是普伐他汀(2.27)、匹伐他汀(2.24)和瑞舒伐他汀(1.83)。结论:基于这些发现,瑞舒伐他汀似乎与ETI表现出弱相互作用,而其他他汀类药物表现出中度相互作用,可能需要适当的剂量减少。这些数据表明,ETI和某些他汀类药物之间存在潜在的临床显著性ddi,需要进行临床研究来验证这些发现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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