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The effects of itraconazole on the pharmacokinetics of rovatirelin were investigated in an open‐label, single‐sequence drug‐drug 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‐drug interaction potential of rovatirelin as a victim. With coadministration, maximum concentration (Cmax) and area under the concentration‐time curve extrapolated to infinity (AUCinf) of rovatirelin increased 3.05‐fold and 2.82‐fold, respectively, and the 90% confidence intervals of the ratios for Cmax (2.64‐3.52) and AUCinf (2.47‐3.23) did not fall within the 0.8‐1.25 boundaries. Urinary excretion of rovatirelin increased at almost the same ratio as the AUCinf ratio with coadministration; however, renal clearance did not change. Cmax, AUCinf, and urinary excretion of TAMP were decreased by coadministration. Itraconazole has the potential to inhibit drug transport via intestinal P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP); therefore, substrate assessments of rovatirelin for the 2 transporters were evaluated using Caco‐2 cell monolayers. In vitro studies showed that rovatirelin is a substrate for P‐gp 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‐gp. [ABSTRACT FROM AUTHOR]