{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:51:15Z","timestamp":1772999475210,"version":"3.50.1"},"reference-count":19,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":54,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["JPMXS0441500025"],"award-info":[{"award-number":["JPMXS0441500025"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Case Reports in Oncological Medicine"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Apalutamide (Apa) is a key therapeutic agent for prostate cancer. Despite its efficacy, Apa is known to induce several drug\u2010metabolizing enzymes including cytochrome P450 3A4 (CYP3A4), raising concerns about drug\u2013drug interactions (DDIs). This study reports a rare case of a sustained DDI between Apa and cyclosporine (CsA)\u2014a CYP3A4 substrate\u2014in a patient with metastatic hormone\u2010sensitive prostate cancer (mHSPC) and primary pure red cell aplasia (PRCA). We further investigated whether Apa could activate pregnane X receptor (PXR), a key nuclear receptor that regulates CYP3A4 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>With informed consent, residual blood samples were used to measure serum Apa concentration. To assess the potential of Apa in activating PXR, a reporter gene assay and a CYP3A4 mRNA induction test were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case Presentation<\/jats:title>\n                    <jats:p>\n                      A 75\u2010year\u2010old man with mHSPC was treated with Apa and leuprorelin. He developed PRCA and was administered CsA (5\u2009mg\/kg\/day) on Day 1. Despite a target trough concentration (\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>trough<\/jats:sub>\n                      ) of 150\u2013200\u2009ng\/mL, the\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>trough<\/jats:sub>\n                      of CsA remained subtherapeutic (34\u2009ng\/mL on Day 5), even after dose escalation to 10\u2009mg\/kg\/day (\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>trough<\/jats:sub>\n                      : 66\u2009ng\/mL on Day 7), suspecting a DDI with Apa. On Day 8, Apa was discontinued and the CsA dosage was reduced to 5\u2009mg\/kg\/day. The Apa concentrations measured on Days 13, 26, and 34 were 1.1, 0.15, and 0.07\u2009\n                      <jats:italic>\u03bc<\/jats:italic>\n                      g\/mL, respectively, and the\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>trough<\/jats:sub>\n                      of CsA increased to 45, 82, and 134\u2009ng\/mL, respectively. In vitro experiments demonstrated that Apa was a strong activator of PXR and capable of inducing\n                      <jats:italic>CYP3A4<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Apa induced CYP3A4 via the PXR pathway, leading to a sustained DDI with CsA. Careful monitoring is necessary when Apa is coadministered with CYP3A4 substrates.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/crom\/3539500","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:13:37Z","timestamp":1772990017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sustained Drug\u2013Drug Interaction Between Cyclosporine and Apalutamide in a Patient With Metastatic Hormone\u2010Sensitive Prostate Cancer: A Case Report and Evaluation of CYP3A4 Induction via Pregnane X Receptor Activation by Apalutamide"],"prefix":"10.1155","volume":"2026","author":[{"given":"Yoshihisa","family":"Mimura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaomi","family":"Sanda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0584-3712","authenticated-orcid":false,"given":"Rei","family":"Unno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Furukawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryota","family":"Shizu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kotona","family":"Motokatsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuusuke","family":"Tashiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiko","family":"Tasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Sugiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoya","family":"Yasujima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7638-6048","authenticated-orcid":false,"given":"Taku","family":"Naiki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Horita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Hotta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Yuasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouichi","family":"Yoshinari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Yasui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinsuke","family":"Iida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2126-5652","authenticated-orcid":false,"given":"Yoko","family":"Furukawa-Hibi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"e_1_2_10_1_2","unstructured":"The Editorial Board of the Cancer Statistics in Japan Cancer Statistics in Japan 2025."},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21820"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1903307"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1715546"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1080\/14737140.2024.2328778"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-020-00882-2"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e328364db84"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1177\/0091270007299930"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07216.x"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1704174"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2024.103736"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.21.12208"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3703"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.5414\/CP204198"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2024.102103"},{"key":"e_1_2_10_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00808-7"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.6004\/jadpro.2019.10.5.8"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023010587"},{"key":"e_1_2_10_19_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra032424"}],"container-title":["Case Reports in Oncological Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/crom\/3539500","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/crom\/3539500","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/crom\/3539500","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:13:39Z","timestamp":1772990019000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/crom\/3539500"}},"subtitle":[],"editor":[{"given":"Jose I.","family":"Mayordomo","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":19,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/crom\/3539500"],"URL":"https:\/\/doi.org\/10.1155\/crom\/3539500","archive":["Portico"],"relation":{},"ISSN":["2090-6706","2090-6714"],"issn-type":[{"value":"2090-6706","type":"print"},{"value":"2090-6714","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2025-10-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"3539500"}}