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Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co\u2010administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in \u22672\u2009year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in &lt;2\u2009year olds which may be due to missing mechanistic understanding of gut physiology and\/or protein binding in very young children. Model predictions for \u22672\u2009year olds showed that entrectinib AUC(0\u2212<jats:italic>t<\/jats:italic>) was increased by approximately sevenfold and five to threefold by strong and high\u2010moderate and low\u2010moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies.<\/jats:p>","DOI":"10.1002\/cpt.3386","type":"journal-article","created":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T13:56:39Z","timestamp":1721310999000},"page":"1130-1140","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>PBPK<\/scp> Modeling of Entrectinib and Its Active Metabolite to Derive Dose Adjustments in Pediatric Populations Co\u2010Administered with <scp>CYP3A4<\/scp> Inhibitors"],"prefix":"10.1002","volume":"116","author":[{"given":"Kenichi","family":"Umehara","sequence":"first","affiliation":[{"name":"Roche Pharmaceutical Research and Early Development Roche Innovation Center, F. Hoffmann\u2010La Roche Ltd.  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