{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:14:40Z","timestamp":1780514080474,"version":"3.54.1"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T00:00:00Z","timestamp":1600387200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and\/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N\u00a0=\u00a022) with B\u2010cell malignancies received single doses of EE\/LN (30\/150\u00a0\u03bcg) and bupropion\/midazolam (75\/2\u00a0mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560\u00a0mg\/day for\u00a0\u2265\u00a02\u00a0weeks. Intestinal CYP3A inhibition was assessed on day 8 (single\u2010dose ibrutinib plus single\u2010dose midazolam). Systemic induction was assessed at steady\u2010state on days 22 (EE\/LN plus ibrutinib) and 24 (bupropion\/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test\/reference) for maximum plasma concentration (C<jats:sub>max<\/jats:sub>) and area under the plasma concentration\u2010time curve (AUC) were derived using linear mixed\u2010effects models (90% confidence interval within 80%\u2010125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was\u00a0\u2264\u00a020% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady\u2010state, the C<jats:sub>max<\/jats:sub>and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4\/2B6, as assessed using EE, LN, midazolam, and bupropion.<\/jats:p>","DOI":"10.1002\/prp2.649","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T13:17:30Z","timestamp":1600435050000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6"],"prefix":"10.1002","volume":"8","author":[{"given":"Jan","family":"de Jong","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Janssen Research &amp; Development LLC San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mitselos","sequence":"additional","affiliation":[{"name":"Clinical Research Oncology Janssen Research &amp; Development LLC Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Jurczak","sequence":"additional","affiliation":[{"name":"Maria Sklodowska\u2010Curie National Institute of Oncology Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul","family":"Cordoba","sequence":"additional","affiliation":[{"name":"Lymphoma Unit Department of Hematology Fundacion Jimenez Diaz University Hospital Madrid Spain"},{"name":"Health Research Institute IIS\u2010FJD Madrid Spain"},{"name":"START Madrid Phase 1 Clinical Trials Unit Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Panizo","sequence":"additional","affiliation":[{"name":"Department of Hematology Cl\u00ednica Universidad de Navarra Pamplona Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Navarra Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Wrobel","sequence":"additional","affiliation":[{"name":"Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation Wroclaw Medical University Wroclaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Dlugosz\u2010Danecka","sequence":"additional","affiliation":[{"name":"Maria Sklodowska\u2010Curie National Institute of Oncology Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Jiao","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Janssen Research &amp; Development LLC Raritan NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juthamas","family":"Sukbuntherng","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC an AbbVie company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Ouellet","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Janssen Research &amp; Development LLC Spring House PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hellemans","sequence":"additional","affiliation":[{"name":"Clinical Research Oncology Janssen Research &amp; Development LLC Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9,18]]},"reference":[{"key":"e_1_2_12_2_1","unstructured":"IMBRUVICA\u00ae (ibrutinib).[prescribing information]. Pharmacyclics LLC Sunnyvale CA; Janssen Biotech Inc. Horsham PA USA; 2019."},{"key":"e_1_2_12_3_1","unstructured":"IMBRUVICA (ibrutinib) [summary of product characteristics]. Janssen\u2010Cilag International NV Beerse Belgium;2019.https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/imbruvica\u2010epar\u2010product\u2010information_en.pdf"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.060061"},{"issue":"7","key":"e_1_2_12_5_1","first-page":"483","article-title":"Ibrutinib (IMBRUVICA): a novel targeted therapy for chronic lymphocytic leukemia","volume":"39","author":"Parmar S","year":"2014","journal-title":"P T"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.4155\/bio.15.159"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2018.1460474"},{"issue":"4","key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"e00156","DOI":"10.1002\/prp2.156","article-title":"Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants","volume":"3","author":"de Jong J","year":"2015","journal-title":"Pharmacol Res Perspect"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.419"},{"key":"e_1_2_12_10_1","unstructured":"Committee for Human Medicinal Products (CHMP).Guideline on the investigation of drug interactions. 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