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Ivosidenib is an inducer of the CYP2B6, CYP2C8, CYP2C9, and CYP3A4 and an inhibitor of P\u2010glycoprotein (P\u2010gp), organic anion transporting polypeptide\u20101B1\/1B3 (OATP1B1\/1B3), and organic anion transporter\u20103 (OAT3) in vitro. A physiologically\u2010based pharmacokinetic (PK) model was developed to predict drug\u2010drug interactions (DDIs) of ivosidenib in patients with AML. The in vivo CYP3A4 induction effect of ivosidenib was quantified using 4\u03b2\u2010hydroxycholesterol and was subsequently verified with the PK data from an ivosidenib and venetoclax combination study. The verified model was prospectively applied to assess the effect of multiple doses of ivosidenib on a sensitive CYP3A4 substrate, midazolam. The simulated midazolam geometric mean area under the curve (AUC) and maximum plasma concentration (C<jats:sub>max<\/jats:sub>) ratios were 0.18 and 0.27, respectively, suggesting ivosidenib is a strong inducer. The model was also used to predict the DDIs of ivosidenib with CYP2B6, CYP2C8, CYP2C9, P\u2010gp, OATP1B1\/1B3, and OAT3 substrates. The AUC ratios following multiple doses of ivosidenib and a single dose of CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 (warfarin), P\u2010gp (digoxin), OATP1B1\/1B3 (rosuvastatin), and OAT3 (methotrexate) substrates were 0.90, 0.52, 0.84, 1.01, 1.02, and 1.27, respectively. Finally, in accordance with regulatory guidelines, the Simcyp modeling platform was qualified to predict CYP3A4 induction using known inducers and sensitive substrates.<\/jats:p>","DOI":"10.1002\/psp4.12619","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T15:27:19Z","timestamp":1617722839000},"page":"577-588","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["PBPK modeling to predict drug\u2010drug interactions of ivosidenib as a perpetrator in cancer patients and qualification of the Simcyp platform for CYP3A4 induction"],"prefix":"10.1002","volume":"10","author":[{"given":"Jayaprakasam","family":"Bolleddula","sequence":"first","affiliation":[{"name":"Agios Pharmaceuticals, Inc Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Ke","sequence":"additional","affiliation":[{"name":"Simcyp Ltd Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Yang","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals, Inc Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra","family":"Prakash","sequence":"additional","affiliation":[{"name":"Agios Pharmaceuticals, Inc Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1773"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.14218\/JERP.2016.00019"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.7b00421"},{"key":"e_1_2_9_5_1","unstructured":"Ivosidenib label.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/211192s001lbl.pdf. 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