{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T12:39:10Z","timestamp":1775651950931,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2017,11,28]],"date-time":"2017-11-28T00:00:00Z","timestamp":1511827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase and is used for the treatment of non\u2010small\u2010cell lung cancer (NSCLC) with activating <jats:italic>EGFR<\/jats:italic> mutations. Gefitinib is metabolized by CYP2D6 and CYP3A4. This analysis compared the systemic exposure of gefitinib after oral administration in <jats:italic>CYP2D6<\/jats:italic> ultrarapid metabolizers (UM) vs extensive metabolizers (EM). Physiologically based pharmacokinetic (PBPK) modeling was conducted using a population\u2010based simulator. The model was calibrated using itraconazole\u2010gefitinib clinical drug\u2010drug interaction data and validated with gefitinib data in <jats:italic>CYP2D6<\/jats:italic> EM vs poor metabolizers (PM). System components of the PBPK model were evaluated using published clinical metoprolol pharmacokinetic data in <jats:italic>CYP2D6<\/jats:italic> UM, EM, and PM. Our PBPK model predicted a gefitinib geometric least\u2010squares mean area under the plasma concentration\u2010time curve (AUC) from time 0 to 264 hours (AUC<jats:sub>(0\u2010264)<\/jats:sub>) ratio in the presence vs absence of itraconazole of 1.85, similar to the ratio of 1.78 from clinical study data. Predicted and observed metoprolol geometric least\u2010squares mean AUC<jats:sub>(0\u201024)<\/jats:sub> ratios in UM vs EM were also similar (0.46 and 0.55, respectively), suggesting that system components related to <jats:italic>CYP2D6<\/jats:italic> in the PBPK model were properly established. In addition, the PBPK model also captured gefitinib pharmacokinetic profiles in <jats:italic>CYP2D6<\/jats:italic> polymorphic populations. The final PBPK model predicted a decrease in gefitinib AUC of \u223c39% in <jats:italic>CYP2D6<\/jats:italic> UM vs EM. Such changes in exposure will have limited impact as the reduced exposure is still above gefitinib's in vitro IC<jats:sub>90<\/jats:sub> for <jats:italic>EGFR<\/jats:italic> activating mutations in NSCLC patients.<\/jats:p>","DOI":"10.1002\/jcph.1036","type":"journal-article","created":{"date-parts":[[2017,11,29]],"date-time":"2017-11-29T17:11:04Z","timestamp":1511975464000},"page":"485-493","source":"Crossref","is-referenced-by-count":20,"title":["Physiologically Based Pharmacokinetic Modeling to Evaluate the Systemic Exposure of Gefitinib in <i>CYP2D6<\/i> Ultrarapid Metabolizers and Extensive Metabolizers"],"prefix":"10.1002","volume":"58","author":[{"given":"Yingxue","family":"Chen","sequence":"first","affiliation":[{"name":"Quantitative Clinical Pharmacology AstraZeneca  Waltham MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diansong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology AstraZeneca  Waltham MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weifeng","family":"Tang","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology AstraZeneca  Gaithersburg MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wangda","family":"Zhou","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology AstraZeneca  Waltham MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nidal","family":"Al\u2010Huniti","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology AstraZeneca  Waltham MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Masson","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology AstraZeneca  Waltham MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,11,28]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.198"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040938"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099314"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.36.8456"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0909530"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70364-X"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810699"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(11)70393-X"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(13)70604-1"},{"issue":"18","key":"e_1_2_9_11_1","article-title":"LUX\u2010Lung 3: a randomized, open\u2010label, phase III study of afatinib versus pemetrexed and cisplatin as first\u2010line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR\u2010activating mutations","volume":"30","author":"Yang JC\u2010H","year":"2012","journal-title":"J Clin Oncol (Meeting Abstracts"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(11)70184-X"},{"key":"e_1_2_9_13_1","unstructured":"National Institute for Health and Care Excellence.EGFR\u2010TK mutation testing in adults with locally advanced or metastatic non\u2010small\u2010cell lung cancer.2013.http:\/\/www.nice.org.uk\/guidance\/dg9. 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