{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:53:47Z","timestamp":1790805227133,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T00:00:00Z","timestamp":1699833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Evaluating Drug\u2010Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady\u2010state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4\u2010component transporter cocktail. This open\u2010label, non\u2010randomized, 2\u2010period fixed\u2010sequence phase I trial compared transporter cocktail (0.25\u00a0mg digoxin\/1\u00a0mg furosemide\/10\u00a0mg metformin hydrochloride\/10\u00a0mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18\u201055 years with body mass index 18.5\u201029.9\u00a0kg\/m<jats:sup>2<\/jats:sup>. During reference treatment\/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment\/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration\u2010time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC<jats:sub>0\u2010\u221e<\/jats:sub>) and the maximum measured concentration of the analyte in plasma (C<jats:sub>max<\/jats:sub>), and the secondary endpoint was the area under the concentration\u2010time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC<jats:sub>0\u2010tz<\/jats:sub>). Steady\u2010state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (\u22122% to \u22129%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2\/MATE\u20101\/MATE\u20102K, OAT1\/OAT3, OATP1B1\/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I\/III (OATP1B1\/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC<jats:sub>0\u2010\u221e<\/jats:sub>\/C<jats:sub>max<\/jats:sub>\/AUC<jats:sub>0\u2010tz<\/jats:sub>) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug\u2010transporter interactions in vivo.<\/jats:p>","DOI":"10.1002\/cpdd.1344","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T07:31:24Z","timestamp":1699947084000},"page":"197-207","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Effect of BI 730357 (Retinoic Acid\u2010Related Orphan Receptor Gamma t Antagonist, Bevurogant) on the Pharmacokinetics of a Transporter Probe Cocktail, Including Digoxin, Furosemide, Metformin, and Rosuvastatin: An Open\u2010Label, Non\u2010randomized, 2\u2010Period Fixed\u2010Sequence Trial in Healthy Subjects"],"prefix":"10.1002","volume":"13","author":[{"given":"HeeJae","family":"Choi","sequence":"first","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals Inc.  Ridgefield CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenglei","family":"Huang","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals Inc.  Ridgefield CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Flack","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharmaceuticals Inc.  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