{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T12:12:29Z","timestamp":1752667949029},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,9,24]],"date-time":"2019-09-24T00:00:00Z","timestamp":1569283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"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":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:p>A phase I, open\u2010label study (<jats:styled-content style=\"fixed-case\">NCT<\/jats:styled-content>02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (<jats:styled-content style=\"fixed-case\">EGFR<\/jats:styled-content>)\u2010mutated non\u2010small cell lung cancer and disease progression post\u2010<jats:styled-content style=\"fixed-case\">EGFR<\/jats:styled-content> tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40\u00a0mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3\u201332. At baseline, both patients had abnormal liver function tests (<jats:styled-content style=\"fixed-case\">LFT<\/jats:styled-content>s; Child\u2010Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~\u00a010\u2010fold) exposure compared with all other patients. Following 31\u00a0days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration\u2010time curve from zero to infinity (AUC) and maximum plasma concentration (C<jats:sub>max<\/jats:sub>)) and <jats:styled-content style=\"fixed-case\">LFT<\/jats:styled-content>s, such as alanine transaminase, aspartate aminotransferase, and bilirubin normalized to population mean values. Additionally, ~\u00a050% and ~\u00a080% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively. High simvastatin exposure on D1 likely resulted from impairment of hepatic first pass metabolism due to liver metastases. Reduction in hepatic disease burden due to osimertinib treatment likely resulted in liver function returning to normal levels.<\/jats:p>","DOI":"10.1111\/cts.12688","type":"journal-article","created":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T14:55:45Z","timestamp":1568040945000},"page":"41-46","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Impact of Disease and Treatment Response in Drug\u2013Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non\u2010Small Cell Lung Cancer"],"prefix":"10.1111","volume":"13","author":[{"given":"Karthick","family":"Vishwanathan","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Safety Sciences Research &amp; Development AstraZeneca Waltham Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mireille","family":"Cantarini","sequence":"additional","affiliation":[{"name":"Oncology Research &amp; Development AstraZeneca Macclesfield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"So","sequence":"additional","affiliation":[{"name":"Oncology Research &amp; Development AstraZeneca Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Masson","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Safety Sciences Research &amp; Development AstraZeneca Waltham Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Fetterolf","sequence":"additional","affiliation":[{"name":"BioPharmaceuticals Research &amp; Development AstraZeneca Gaithersburg Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh S.","family":"Ramalingam","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute of Emory University Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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