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Pharmacokinetic Drug Interactions of an Orally Available TRH Analog (Rovatirelin) With a CYP3A4/5 and PâGlycoprotein Inhibitor (Itraconazole)
- Source :
- The Journal of Clinical Pharmacology. 60:1314-1323
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
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.
- 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
Subjects
Details
- ISSN :
- 15524604 and 00912700
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- The Journal of Clinical Pharmacology
- Accession number :
- edsair.doi.dedup.....445b1ecb7c5a250abf7dc69d202fe858