{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T02:24:21Z","timestamp":1783045461234,"version":"3.54.6"},"reference-count":28,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CHA University\u2019s Industry Academic Cooperation Foundation Fund","award":["CHA-202301140001"],"award-info":[{"award-number":["CHA-202301140001"]}]},{"name":"CHA University\u2019s Industry Academic Cooperation Foundation Fund","award":["BERING21AO"],"award-info":[{"award-number":["BERING21AO"]}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CHA-202301140001"],"award-info":[{"award-number":["CHA-202301140001"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["BERING21AO"],"award-info":[{"award-number":["BERING21AO"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Anton Yelchin Foundation","award":["CHA-202301140001"],"award-info":[{"award-number":["CHA-202301140001"]}]},{"name":"Anton Yelchin Foundation","award":["BERING21AO"],"award-info":[{"award-number":["BERING21AO"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The increasing use of statins in people with cystic fibrosis (CF) necessitates the investigation of potential drug\u2013drug 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics17030318","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T07:37:17Z","timestamp":1740987437000},"page":"318","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evaluation of Complex Drug Interactions Between Elexacaftor-Tezacaftor-Ivacaftor and Statins Using Physiologically Based Pharmacokinetic Modeling"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6696-3948","authenticated-orcid":false,"given":"Eunjin","family":"Hong","sequence":"first","affiliation":[{"name":"College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Republic of Korea"},{"name":"Gradute School of Clinical Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si 13488, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Chung","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, 1975 Zonal Ave, Los Angeles, CA 90033, USA"},{"name":"USC Anton Yelchin CF Clinic, 1510 San Pablo St., Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adupa P.","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, 1975 Zonal Ave, Los Angeles, CA 90033, USA"},{"name":"USC Anton Yelchin CF Clinic, 1510 San Pablo St., Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3744-3310","authenticated-orcid":false,"given":"Paul M.","family":"Beringer","sequence":"additional","affiliation":[{"name":"USC Anton Yelchin CF Clinic, 1510 San Pablo St., Los Angeles, CA 90033, USA"},{"name":"Department of Clinical Pharmacy, Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104","DOI":"10.5500\/wjt.v10.i5.104","article-title":"Chronic lung allograft dysfunction post-lung transplantation: The era of bronchiolitis obliterans syndrome and restrictive allograft syndrome","volume":"10","author":"Yoshiyasu","year":"2020","journal-title":"World J. Transplant."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.healun.2017.05.007","article-title":"Perioperative statin use is associated with decreased incidence of primary graft dysfunction after lung transplantation","volume":"36","author":"Raphael","year":"2017","journal-title":"J. Heart Lung Transplant."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.2174\/1573403X13666170426104611","article-title":"The Anti-Inflammatory Effects of Statins on Coronary Artery Disease: An Updated Review of the Literature","volume":"13","author":"Diamantis","year":"2017","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_4","first-page":"100276","article-title":"Obesity in cystic fibrosis","volume":"26","author":"Kutney","year":"2021","journal-title":"J. Clin. Transl. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e220740","DOI":"10.1001\/jamanetworkopen.2022.0740","article-title":"Association of Body Mass Index with Clinical Outcomes in Patients with Cystic Fibrosis: A Systematic Review and Meta-analysis","volume":"5","author":"Nagy","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_6","first-page":"100290","article-title":"Cystic fibrosis-related diabetes: Prevalence, screening, and diagnosis","volume":"27","author":"Khare","year":"2022","journal-title":"J. Clin. Transl. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/S2213-2600(23)00324-7","article-title":"Understanding and addressing the needs of people with cystic fibrosis in the era of CFTR modulator therapy","volume":"11","author":"Hisert","year":"2023","journal-title":"Lancet Respir. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e468","DOI":"10.1161\/CIR.0000000000000456","article-title":"Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease: A Scientific Statement from the American Heart Association","volume":"134","author":"Wiggins","year":"2016","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.clpt.2006.09.003","article-title":"Drug interactions with lipid-lowering drugs: Mechanisms and clinical relevance","volume":"80","author":"Neuvonen","year":"2006","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1080\/17425255.2023.2220960","article-title":"Drug-drug interactions involving CFTR modulators: A review of the evidence and clinical implications","volume":"19","author":"Hong","year":"2023","journal-title":"Expert. Opin. Drug Metab. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.jacl.2022.05.068","article-title":"NLA scientific statement on statin intolerance: A new definition and key considerations for ASCVD risk reduction in the statin intolerant patient","volume":"16","author":"Cheeley","year":"2022","journal-title":"J. Clin. Lipidol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1002\/cpt.2585","article-title":"Physiologically-Based Pharmacokinetic-Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor-Tezacaftor-Ivacaftor with Nirmatrelvir-Ritonavir for the Treatment of COVID-19","volume":"111","author":"Hong","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hong, E., Carmanov, E., Shi, A., Chung, P.S., Rao, A.P., Forrester, K., and Beringer, P.M. (2023). Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions between Elexacaftor\/Tezacaftor\/Ivacaftor and Tacrolimus in Lung Transplant Recipients. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15051438"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1124\/dmd.32.6.647","article-title":"Validated assays for human cytochrome P450 activities","volume":"32","author":"Walsky","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_15","first-page":"106362","article-title":"Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs","volume":"181","author":"Deng","year":"2023","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_16","unstructured":"CFF (2024, May 20). Cystic Fibrosis Foundation Patient Registry 2020 Annual Data Report. Available online: https:\/\/www.cff.org\/sites\/default\/files\/2021-10\/2019-Patient-Registry-Annual-Data-Report.pdf."},{"key":"ref_17","unstructured":"FDA (2024, April 01). Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review(s), Ivacaftor, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2012\/203188Orig1s000ClinPharmR.pdf."},{"key":"ref_18","unstructured":"FDA (2024, April 02). Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review(s), Tezacaftor\/Ivacaftor, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2018\/210491Orig1s000ClinPharmR.pdf."},{"key":"ref_19","unstructured":"FDA (2024, March 30). Center for Drug Evaluation and Research. Multi-Discipline Review, Elexacaftor\/Tezacaftor\/Ivacaftor, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2019\/212273Orig1s000MultidisciplineR.pdf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1124\/dmd.110.032177","article-title":"Confidence assessment of the Simcyp time-based approach and a static mathematical model in predicting clinical drug-drug interactions for mechanism-based CYP3A inhibitors","volume":"38","author":"Wang","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1124\/jpet.104.082826","article-title":"CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions","volume":"314","author":"Galetin","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/dmd.121.000401","article-title":"Pharmacokinetic Drug-Drug Interactions with Drugs Approved by the US Food and Drug Administration in 2020: Mechanistic Understanding and Clinical Recommendations","volume":"50","author":"Yu","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1124\/dmd.120.000149","article-title":"Calibrating the In Vitro-In Vivo Correlation for OATP-Mediated Drug-Drug Interactions with Rosuvastatin Using Static and PBPK Models","volume":"48","author":"Sane","year":"2020","journal-title":"Drug Metab. Dispos."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/clpt.2012.163","article-title":"Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: It\u2019s not just about OATP1B1","volume":"92","author":"Elsby","year":"2012","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Shah, N.R., Bulitta, J.B., Kinzig, M., Landersdorfer, C.B., Jiao, Y., Sutaria, D.S., Tao, X., H\u00f6hl, R., Holzgrabe, U., and Kees, F. (2019). Novel Population Pharmacokinetic Approach to Explain the Differences between Cystic Fibrosis Patients and Healthy Volunteers via Protein Binding. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11060286"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.nutres.2014.10.007","article-title":"Increase in body mass index from normal weight to overweight in a cross-sectional sample of healthy research volunteers","volume":"34","author":"Courville","year":"2014","journal-title":"Nutr. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5013","DOI":"10.1128\/AAC.49.12.5013-5017.2005","article-title":"Absolute bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fbrosis","volume":"49","author":"Beringer","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1007\/s40262-020-00932-9","article-title":"Pharmacokinetics in patients with cystic fibrosis: A systematic review of data published between 1999 and 2019","volume":"59","author":"Gasthuys","year":"2020","journal-title":"Clin. Pharmacokinet."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/3\/318\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:45:38Z","timestamp":1760028338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/3\/318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,1]]},"references-count":28,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["pharmaceutics17030318"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17030318","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,1]]}}}