{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T16:54:27Z","timestamp":1775235267935,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T00:00:00Z","timestamp":1590537600000},"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":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The effects of itraconazole on the pharmacokinetics of rovatirelin were investigated in an open\u2010label, single\u2010sequence drug\u2010drug interaction study in 16 healthy subjects. Subjects were administered a single oral dose of rovatirelin (1.6 mg) on day 1 and day 15. From day 8 through 16, subjects received daily oral doses of itraconazole (200 mg\/day). Concentrations of rovatirelin and (thiazolylalanyl)methylpyrrolidine (TAMP), the major metabolite of rovatirelin formed by cytochrome P450 (CYP) 3A4\/5, were determined in plasma and urine. Pharmacokinetic parameters were used to evaluate the drug\u2010drug interaction potential of rovatirelin as a victim. With coadministration, maximum concentration (C<jats:sub>max<\/jats:sub>) and area under the concentration\u2010time curve extrapolated to infinity (AUC<jats:sub>inf<\/jats:sub>) of rovatirelin increased 3.05\u2010fold and 2.82\u2010fold, respectively, and the 90% confidence intervals of the ratios for C<jats:sub>max<\/jats:sub> (2.64\u20103.52) and AUC<jats:sub>inf<\/jats:sub> (2.47\u20103.23) did not fall within the 0.8\u20101.25 boundaries. Urinary excretion of rovatirelin increased at almost the same ratio as the AUC<jats:sub>inf<\/jats:sub> ratio with coadministration; however, renal clearance did not change. C<jats:sub>max<\/jats:sub>, AUC<jats:sub>inf<\/jats:sub>, and urinary excretion of TAMP were decreased by coadministration. Itraconazole has the potential to inhibit drug transport via intestinal P\u2010glycoprotein (P\u2010gp) and breast cancer resistance protein (BCRP); therefore, substrate assessments of rovatirelin for the 2 transporters were evaluated using Caco\u20102 cell monolayers. In vitro studies showed that rovatirelin is a substrate for P\u2010gp but not for BCRP. The current study shows that itraconazole's effect on rovatirelin pharmacokinetics is mediated through inhibition of CYP3A4\/5 and intestinal P\u2010gp.<\/jats:p>","DOI":"10.1002\/jcph.1628","type":"journal-article","created":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T20:35:47Z","timestamp":1590611747000},"page":"1314-1323","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pharmacokinetic Drug Interactions of an Orally Available TRH Analog (Rovatirelin) With a CYP3A4\/5 and P\u2010Glycoprotein Inhibitor (Itraconazole)"],"prefix":"10.1002","volume":"60","author":[{"given":"Kaoru","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Central Research Laboratories Kissei Pharmaceutical Co, Ltd.  Azumino Nagano Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshikazu","family":"Abe","sequence":"additional","affiliation":[{"name":"Central Research Laboratories Kissei Pharmaceutical Co, Ltd.  Azumino Nagano Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asuka","family":"Kawai","sequence":"additional","affiliation":[{"name":"Clinical Development Division Kissei Pharmaceutical Co, Ltd.  Bunkyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takao","family":"Furihata","sequence":"additional","affiliation":[{"name":"Clinical Development Division Kissei Pharmaceutical Co, Ltd.  Bunkyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuro","family":"Endo","sequence":"additional","affiliation":[{"name":"Central Research Laboratories Kissei Pharmaceutical Co, Ltd.  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