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This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID\u201019) with nirmatrelvir\u2010ritonavir\u00a0in people with cystic fibrosis (CF) due to the potential for significant drug\u2013drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID\u201019 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A\u2010mediated DDI of elexacaftor\u2010tezacaftor\u2010ivacaftor was evaluated using a physiologically\u2010based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug\u2010dependent parameters of elexacaftor\u2010tezacaftor\u2010ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor\u2010tezacaftor\u2010ivacaftor. The elexacaftor\u2010tezacaftor\u2010ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor\u2010tezacaftor\u2010ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor\u2010tezacaftor\u2010ivacaftor should be reduced when coadministered with nirmatrelvir\u2010ritonavir\u00a0to elexacaftor 200 mg\u2013tezacaftor 100 mg\u2013ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full\u2010dose elexacaftor\u2010tezacaftor\u2010ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism\u2010based inhibitor. The simulation predicts a regimen of elexacaftor\u2010tezacaftor\u2010ivacaftor administered concomitantly with nirmatrelvir\u2010ritonavir in people with CF that will likely decrease the impact of the drug interaction.<\/jats:p>","DOI":"10.1002\/cpt.2585","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T04:10:01Z","timestamp":1647403801000},"page":"1324-1333","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Physiologically\u2010Based Pharmacokinetic\u2010Led Guidance for Patients With Cystic Fibrosis Taking Elexacaftor\u2010Tezacaftor\u2010Ivacaftor With Nirmatrelvir\u2010Ritonavir for the Treatment of COVID\u201019"],"prefix":"10.1111","volume":"111","author":[{"given":"Eunjin","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy School of Pharmacy University of Southern California Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Almond","sequence":"additional","affiliation":[{"name":"Simcyp Division Certara UK Ltd Sheffield UK"}],"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 Los Angeles California USA"},{"name":"University of Southern California, Anton Yelchin Cystic Fibrosis Clinic Los Angeles California 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 Los Angeles California USA"},{"name":"University of Southern California, Anton Yelchin Cystic Fibrosis Clinic Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Beringer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy School of Pharmacy University of Southern California Los Angeles California USA"},{"name":"University of Southern California, Anton Yelchin Cystic Fibrosis Clinic Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32597-8"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12610"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30177-6"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2020.03.037"},{"key":"e_1_2_9_6_1","volume-title":"Paxlovid [Fact Sheet for Healthcare Providers: Emergency Use Authorization for Paxlovid]","author":"Pfizer","year":"2021"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2010.298"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0330-y"},{"key":"e_1_2_9_9_1","unstructured":"US Food and Drug Administration.Guidance for industry: physiologically based pharmacokinetic analyses \u2013 format and content<https:\/\/www.fda.gov\/media\/101469\/download> (2018)."},{"key":"e_1_2_9_10_1","volume-title":"Patient Registry 2020 Annual Data Report","author":"Cystic Fibrosis Foundation","year":"2021"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nutres.2014.10.007"},{"key":"e_1_2_9_12_1","unstructured":"US Food and Drug Administration Center for Drug Evaluation and Research.Clinical pharmacology and biopharmaceutics review(s) Ivacaftor<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2012\/203188Orig1s000ClinPharmR.pdf> (2012)."},{"key":"e_1_2_9_13_1","unstructured":"US Food and Drug Administration Center for Drug Evaluation and Research.Clinical pharmacology and biopharmaceutics review(s) Tezacaftor\/Ivacaftor<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2018\/210491Orig1s000ClinPharmR.pdf>."},{"key":"e_1_2_9_14_1","unstructured":"US Food and Drug Administration. 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