{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:08:53Z","timestamp":1785449333828,"version":"3.56.0"},"reference-count":26,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Pirtobrutinib is a reversible Bruton tyrosine kinase (BTK) inhibitor. In\u00a0vitro, pirtobrutinib is metabolized by cytochrome P450 (CYP) 3A4 and uridine 5\u2032\u2010diphosphoglucuronosyl transferases (UGTs) and causes reversible and time\u2010dependent inhibition and induction of CYP3A4. Coadministration of itraconazole, a strong CYP3A4 inhibitor, with pirtobrutinib in healthy human subjects, resulted in a pirtobrutinib area under the plasma concentration\u2010time curve (AUC) ratio of 1.49, while rifampin, a strong CYP3A4 inducer, decreased pirtobrutinib AUC by 71%. Oral administration of pirtobrutinib 200\u2009mg once daily (QD) increased the AUC of oral and intravenous midazolam by 1.70\u2010 and 1.12\u2010fold, respectively. A physiologically based pharmacokinetic (PBPK) model was developed for pirtobrutinib using physicochemical properties, in\u00a0vitro data, and clinical pharmacology study results. The PBPK model captured the clinically observed interactions for itraconazole, rifampin, and midazolam, with predicted pirtobrutinib and midazolam AUC ratios within 0.91\u2010 to 1.16\u2010fold of observed. The model predicted 1.20\u2010 to 1.73\u2010fold increases in the pirtobrutinib AUC with strong and moderate CYP3A4 inhibitors. Furthermore, the predicted pirtobrutinib AUC ratios were within 0.51\u20130.86 with moderate and weak CYP3A4 inducers. The predicted effects of CYP3A4 modulators on pirtobrutinib pharmacokinetics, together with the known exposure\u2010response relationships for safety and efficacy in patients with hematological malignancies, were used for recommending appropriate dosing regimens during coadministration.<\/jats:p>","DOI":"10.1002\/psp4.70134","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T14:15:06Z","timestamp":1761833706000},"page":"2221-2231","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Application of Physiologically\u2010Based Pharmacokinetic Modeling to Support Drug Labeling: Prediction of\n                    <scp>CYP3A4<\/scp>\n                    \u2010Mediated Pirtobrutinib\u2010Drug Interactions"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8270-7119","authenticated-orcid":false,"given":"Dan\u2010Dan","family":"Tian","sequence":"first","affiliation":[{"name":"Eli Lilly and Company Lilly Corporate Center  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Hall","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Lilly Corporate Center  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6453-2749","authenticated-orcid":false,"given":"Sonya C.","family":"Chapman","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Lilly Corporate Center  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4645-0763","authenticated-orcid":false,"given":"Maria M.","family":"Posada","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company Lilly Corporate Center  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2018.10.033"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1767"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010022\u201003274\u20102"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.13780"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12794"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.2107"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12636"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12449"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1596"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1584"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.8b00129"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/019262339502300203"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.111.040634"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.110.036400"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201042"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.121.000356"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.123.001382"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010016\u20101865\u20109"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3477"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108459"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.104.000794"},{"key":"e_1_2_9_23_1","unstructured":"P. M. S.Yerino B.Ogilvie andD. B.Buckley \u201cThe In\u00a0Vitro Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4\/5 Inhibitors (Ritonavir Clarithromycin and Itraconazole) as Inhibitors of Non\u2010CYP Enzymes \u201daccessed October 5 https:\/\/www.xenotech.com\/wp\u2010content\/uploads\/2020\/05\/ISSX_In\u2010Vitro\u2010Ketoconazole\u2010Clinical\u2010CYP3A45\u2010Inhibitors\u2010Ritonavir\u2010Clarithromycin\u2010Itraconazole\u2010Non\u2010CYP\u2010Enzymes.pdf."},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.118.081927"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.32.1.140"},{"key":"e_1_2_9_26_1","unstructured":"EMA \u201cGuideline on the Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation \u201d(2018) https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/guideline\u2010reporting\u2010physiologically\u2010based\u2010pharmacokinetic\u2010pbpk\u2010modelling\u2010simulation_en.pdf."},{"key":"e_1_2_9_27_1","unstructured":"FDA \u201cPhysiologically Based Pharmacokinetic Analyses\u2014Format and Content Guidance for Industry \u201d(2018) http:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/UCM531207.pdf."}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70134","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T09:08:00Z","timestamp":1765876080000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70134"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,30]]},"references-count":26,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/psp4.70134"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70134","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,30]]},"assertion":[{"value":"2025-05-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}