1. Pharmacokinetic Drug Interactions of an Orally Available TRH Analog (Rovatirelin) With a CYP3A4/5 and P‐Glycoprotein Inhibitor (Itraconazole)
- Author
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Takuro Endo, Hiroo Takeda, Asuka Kawai, Takao Furihata, Kaoru Kobayashi, and Yoshikazu Abe
- Subjects
Adult ,Male ,Pyrrolidines ,Abcg2 ,Itraconazole ,Metabolite ,Cmax ,Administration, Oral ,Drug Elimination Routes ,Urine ,Pharmacology ,030226 pharmacology & pharmacy ,Permeability ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Asian People ,Pharmacokinetics ,medicine ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Cytochrome P-450 CYP3A ,Humans ,Drug Interactions ,Pharmacology (medical) ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Thyrotropin-Releasing Hormone ,Oxazolidinones ,biology ,CYP3A4 ,Cytochrome P450 ,Biological Transport ,Healthy Volunteers ,Hormones ,Neoplasm Proteins ,chemistry ,Area Under Curve ,030220 oncology & carcinogenesis ,biology.protein ,Cytochrome P-450 CYP3A Inhibitors ,Caco-2 Cells ,medicine.drug - Abstract
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.
- Published
- 2020