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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Kobayashi K, Abe Y, Kawai A, Furihata T, Endo T, and Takeda H
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism, Administration, Oral, Adult, Area Under Curve, Asian People, Biological Transport drug effects, Caco-2 Cells, Cytochrome P-450 CYP3A metabolism, Cytochrome P-450 CYP3A Inhibitors administration & dosage, Cytochrome P-450 CYP3A Inhibitors pharmacology, Drug Elimination Routes drug effects, Healthy Volunteers, Hormones blood, Humans, Itraconazole administration & dosage, Itraconazole pharmacology, Male, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins metabolism, Oxazolidinones administration & dosage, Oxazolidinones adverse effects, Oxazolidinones metabolism, Permeability drug effects, Pyrrolidines administration & dosage, Pyrrolidines adverse effects, Pyrrolidines metabolism, Young Adult, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Cytochrome P-450 CYP3A Inhibitors pharmacokinetics, Drug Interactions, Itraconazole pharmacokinetics, Oxazolidinones pharmacokinetics, Pyrrolidines pharmacokinetics, Thyrotropin-Releasing Hormone analogs & derivatives
- 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 (C
max ) 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., (© 2020, The American College of Clinical Pharmacology.)- Published
- 2020
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