{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:46:54Z","timestamp":1776836814548,"version":"3.51.2"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Anton Yelchin Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Elexacaftor\/tezacaftor\/ivacaftor (ETI) treatment has potential benefits in lung transplant recipients, including improvements in extrapulmonary manifestations, such as gastrointestinal and sinus disease; however, ivacaftor is an inhibitor of cytochrome P450 3A (CYP3A) and may, therefore, pose a risk for elevated systemic exposure to tacrolimus. The aim of this investigation is to determine the impact of ETI on tacrolimus exposure and devise an appropriate dosing regimen to manage the risk of this drug\u2013drug interaction (DDI). The CYP3A-mediated DDI of ivacaftor\u2013tacrolimus was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach, incorporating CYP3A4 inhibition parameters of ivacaftor and in vitro enzyme kinetic parameters of tacrolimus. To further support the findings in PBPK modeling, we present a case series of lung transplant patients who received both ETI and tacrolimus. We predicted a 2.36-fold increase in tacrolimus exposure when co-administered with ivacaftor, which would require a 50% dose reduction of tacrolimus upon initiation of ETI treatment to avoid the risk of elevated systemic exposure. Clinical cases (N = 13) indicate a median 32% (IQR: \u221214.30, 63.80) increase in the dose-normalized tacrolimus trough level (trough concentration\/weight-normalized daily dose) after starting ETI. These results indicate that the concomitant administration of tacrolimus and ETI may lead to a clinically significant DDI, requiring the dose adjustment of tacrolimus.<\/jats:p>","DOI":"10.3390\/pharmaceutics15051438","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T01:06:28Z","timestamp":1683594388000},"page":"1438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Application of Physiologically Based Pharmacokinetic Modeling to Predict Drug\u2013Drug Interactions between Elexacaftor\/Tezacaftor\/Ivacaftor and Tacrolimus in Lung Transplant Recipients"],"prefix":"10.3390","volume":"15","author":[{"given":"Eunjin","family":"Hong","sequence":"first","affiliation":[{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugeniu","family":"Carmanov","sequence":"additional","affiliation":[{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Shi","sequence":"additional","affiliation":[{"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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Forrester","sequence":"additional","affiliation":[{"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":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3744-3310","authenticated-orcid":false,"given":"Paul M.","family":"Beringer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033, USA"},{"name":"USC Anton Yelchin CF Clinic, 1510 San Pablo St, Los Angeles, CA 90033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1016\/S0140-6736(19)32597-8","article-title":"Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomised, phase 3 trial","volume":"394","author":"Heijerman","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1056\/NEJMoa1908639","article-title":"Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele","volume":"381","author":"Middleton","year":"2019","journal-title":"N. 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