{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:45:51Z","timestamp":1747183551475,"version":"3.40.5"},"reference-count":22,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre\u2010clinical profiling suggests that time\u2010dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co\u2010administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time\u2010\/dose\u2010dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Open\u2010label, fixed\u2010sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2\u00a0mg on days 1 and 7 and single oral doses of Atuliflapon (125\u2009mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug\u2013drug interaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mean midazolam values of maximum plasma concentration (C<jats:sub>max<\/jats:sub>) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co\u2010administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in C<jats:sub>max<\/jats:sub> of midazolam following its co\u2010administrations with two predicted therapeutically relevant doses of Atuliflapon.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16131","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T23:45:15Z","timestamp":1717458315000},"page":"2180-2187","source":"Crossref","is-referenced-by-count":1,"title":["A drug\u2013drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5\u2010lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9839-2433","authenticated-orcid":false,"given":"Jane","family":"Kn\u00f6chel","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology &amp; Safety Sciences, BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijender","family":"Panduga","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology &amp; 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