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Mechanistic static modeling suggested vonoprazan is a potential clinically relevant CYP3A inhibitor. Thus, a clinical study was conducted to evaluate the impact of vonoprazan on the exposure of oral midazolam, an index substrate for CYP3A. A physiologically\u2010based pharmacokinetic (PBPK) model for vonoprazan was also developed using in vitro data, drug\u2010 and system\u2010specific parameters, and clinical data and observations from a [<jats:sup>14<\/jats:sup>C] human absorption, distribution, metabolism, and excretion study. The PBPK model was refined and verified using data from a clinical DDI study with the strong CYP3A inhibitor, clarithromycin, to confirm the fraction metabolized by CYP3A, and the oral midazolam clinical DDI data assessing vonoprazan as a time\u2010dependent inhibitor of CYP3A. The verified PBPK model was applied to simulate the anticipated changes in vonoprazan exposure due to moderate and strong CYP3A inducers (efavirenz and rifampin, respectively). The clinical midazolam DDI study indicated weak inhibition of CYP3A, with a less than twofold increase in midazolam exposure. PBPK simulations projected a 50% to 80% reduction in vonoprazan exposure when administered concomitantly with moderate or strong CYP3A inducers. Based on these results, the vonoprazan label was revised and states that lower doses of sensitive CYP3A substrates with a narrow therapeutic index should be used when administered concomitantly with vonoprazan, and co\u2010administration with moderate and strong CYP3A inducers should be avoided.<\/jats:p>","DOI":"10.1002\/psp4.12939","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T10:46:23Z","timestamp":1678445183000},"page":"532-544","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tiered approach to evaluate the <scp>CYP3A<\/scp> victim and perpetrator drug\u2013drug interaction potential for vonoprazan using <scp>PBPK<\/scp> modeling and clinical data to inform labeling"],"prefix":"10.1002","volume":"12","author":[{"given":"Darcy J.","family":"Mulford","sequence":"first","affiliation":[{"name":"Phathom Pharmaceuticals, Inc.  Buffalo Grove Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Ramsden","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Michon","sequence":"additional","affiliation":[{"name":"Certara  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eckhard","family":"Leifke","sequence":"additional","affiliation":[{"name":"Phathom Pharmaceuticals, Inc.  Buffalo Grove Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neila","family":"Smith","sequence":"additional","affiliation":[{"name":"Phathom Pharmaceuticals, Inc.  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