{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:57:59Z","timestamp":1790927879276,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:p>Orforglipron is an orally administered, small\u2010molecule glucagon\u2010like peptide\u20101 receptor agonist in clinical development for the treatment of type 2 diabetes and obesity. Orforglipron is a substrate of CYP3A4, organic anion transporting polypeptides (OATPs) 1B\/1B3, and P\u2010glycoprotein (P\u2010gp); however, precipitants commonly used to define these mechanisms have not been fully characterized. The enzyme\u2010 and transporter\u2010mediated DDI profile of orforglipron and that of CYP3A4\/OATP1B\/P\u2010gp precipitants were characterized in six phase 1 clinical studies in healthy participants. Orforglipron pharmacokinetics were assessed with clarithromycin, carbamazepine, cyclosporine, and quinidine. Precipitant effects on CYP3A and OATP1B activity were measured using midazolam and coproporphyrin\u2010I (CP\u2010I). Orforglipron effects on CYP3A, P\u2010gp, BCRP, and OATP1B were evaluated using midazolam, digoxin, rosuvastatin, simvastatin, atorvastatin, and CP\u2010I. Mechanistic interrogation of the simvastatin interaction was also conducted. Clarithromycin, carbamazepine, and quinidine had minimal effect on CP\u2010I pharmacokinetics, while the cyclosporine effect was substantial. Cyclosporine and quinidine weakly increased midazolam exposure. Orforglipron exposure increased in the presence of clarithromycin and cyclosporine and decreased with carbamazepine, demonstrating orforglipron exposure is affected by precipitants of CYP3A4 and OATP1B. Quinidine\u00a0did not meaningfully change orforglipron exposure. Orforglipron had no clinically meaningful effect on the exposure of midazolam, digoxin, or atorvastatin. A weak increase in rosuvastatin exposure was consistent with BCRP inhibition, as CP\u2010I data confirmed orforglipron does not affect OATP1B. Increase in simvastatin acid exposure was attributed to the unique disposition of simvastatin rather than enzyme or transporter inhibition. These findings address mechanistic precipitant knowledge gaps and provide a framework for managing potential orforglipron DDIs in clinical practice.<\/jats:p>","DOI":"10.1002\/cpt.70377","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T03:28:08Z","timestamp":1783135688000},"page":"979-990","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical Characterization of Enzyme and Transporter Precipitants to Evaluate Drug\u2013Drug Interactions for Orforglipron, a\u00a0Small Molecule Glucagon\u2010Like Peptide\u20101 Receptor Agonist"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2016-9930","authenticated-orcid":false,"given":"Bridget L.","family":"Morse","sequence":"first","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-5623","authenticated-orcid":false,"given":"David E.","family":"Coutant","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6223-8140","authenticated-orcid":false,"given":"Xiaosu","family":"Ma","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohini","family":"Raha","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerthan","family":"Aithal","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Nicoll","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc R. 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