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We assessed gepotidacin as a DDI victim with a potent cytochrome P450 (CYP) 3A4\/P\u2010glycoprotein (P\u2010gp) inhibitor (itraconazole), potent CYP3A4 inducer (rifampicin), and nonspecific organic cation transporter (OCT)\/multidrug and toxic extrusion transporter (MATE) renal transport inhibitor (cimetidine) via single doses of gepotidacin before and after co\u2010administration with multiple doses of the modulator drugs. Gepotidacin DDI perpetrator potential for P\u2010gp inhibition (digoxin) and CYP3A4 inhibition (midazolam) was evaluated via single doses of the two\u2010drug cocktail without and with gepotidacin. The DDI magnitudes were interpreted based on area under the concentration\u2010time curve (AUC). A weak DDI (AUC increase 48%\u201350%) was observed for gepotidacin co\u2010administered with itraconazole. A clinically significant decrease in gepotidacin plasma AUC (52%) was observed with rifampicin coadministration, indicating a moderate DDI. There was no DDI for gepotidacin with cimetidine; a unique biomarker approach showed increased serum creatinine (24%), decreased renal clearance of creatinine (21%), and N1\u2010methylnicotinamide (39%), which confirmed extensive MATE inhibition and partial OCT2 inhibition. Gepotidacin was not a P\u2010gp DDI perpetrator, although the maximum plasma concentration of digoxin increased (53%) and is potentially clinically relevant given its narrow therapeutic index. Gepotidacin demonstrated weak CYP3A4 inhibition with midazolam (&lt;2\u2010fold AUC increase). There were no new safety\u2010risk profile findings. These results will inform the safe and efficacious clinical use of gepotidacin when co\u2010administered with other drugs.<\/jats:p>","DOI":"10.1111\/cts.13477","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T04:59:00Z","timestamp":1673845140000},"page":"647-661","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Clinical assessment of gepotidacin (<scp>GSK2140944<\/scp>) as a victim and perpetrator of <scp>drug\u2013drug<\/scp> interactions via <scp>CYP3A<\/scp> metabolism and transporters"],"prefix":"10.1111","volume":"16","author":[{"given":"Aline","family":"Barth","sequence":"first","affiliation":[{"name":"Global Blood Therapeutics  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline R.","family":"Perry","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaila","family":"Shabbir","sequence":"additional","affiliation":[{"name":"GSK  Stevenage UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej J.","family":"Zamek\u2010Gliszczynski","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebin","family":"Thomas","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Etienne F.","family":"Dumont","sequence":"additional","affiliation":[{"name":"Boston Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darin\u00a0B.","family":"Brimhall","sequence":"additional","affiliation":[{"name":"PPD  Las Vegas Nevada USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dung","family":"Nguyen","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2718-4335","authenticated-orcid":false,"given":"Meenakshi","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"GSK  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4179-4842","authenticated-orcid":false,"given":"Brandon","family":"Swift","sequence":"additional","affiliation":[{"name":"GSK  Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02820-15"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.8b00315"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09197"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00199-20"},{"key":"e_1_2_12_6_1","unstructured":"MushtaqS VickersA SadoukiZ et al.In vitro activities of gepotidacin a novel triazaacenaphthylene topoisomerase IV and DNA gyrase inhibitor against gram\u2010negative bacteria andstaphylococcus saprophyticus poster P1849;2019. 29th European Congress of Clinical Microbiology & Infectious Diseases."},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky162"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02047-16"},{"key":"e_1_2_12_9_1","unstructured":"Hoover J. 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