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Model-based assessments of CYP3A-mediated drug-drug interaction risk of milademetan.

Authors :
Hong Y
Ishizuka T
Watanabe A
Tachibana M
Lee M
Ishizuka H
LaCreta F
Abutarif M
Source :
Clinical and translational science [Clin Transl Sci] 2021 Nov; Vol. 14 (6), pp. 2220-2230. Date of Electronic Publication: 2021 Jun 23.
Publication Year :
2021

Abstract

Milademetan is a small-molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P-glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug-drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development. A clinical DDI study of milademetan (NCT03614455) showed that concomitant administration of single-dose milademetan with the strong CYP3A inhibitor itraconazole or posaconazole increased milademetan mean area under the curve from zero to infinity (AUC <subscript>inf</subscript> ) by 2.15-fold (90% confidence interval [CI], 1.98-2.34) and 2.49-fold (90% CI, 2.26-2.74), respectively, supporting that the milademetan dose should be reduced by 50% when concomitantly administered with strong CYP3A inhibitors. A physiologically-based pharmacokinetic (PBPK) model of milademetan was subsequently developed to predict the magnitude of CYP3A-mediated DDI potential of milademetan with moderate CYP3A inhibitors. The PBPK model predicted an increase in milademetan exposure of 1.72-fold (90% CI, 1.69-1.76) with fluconazole, 1.91-fold (90% CI, 1.83-1.99) with erythromycin, and 2.02-fold (90% CI, 1.93-2.11) with verapamil. In addition, it estimated that milademetan's original dose (160 mg once daily) could be resumed from its half-reduced dose 3 days after discontinuation of concomitant strong CYP3A inhibitors. The established PBPK model of milademetan was qualified and considered to be robust enough to support continued development of milademetan.<br /> (© 2021 Daiichi Sankyo Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Details

Language :
English
ISSN :
1752-8062
Volume :
14
Issue :
6
Database :
MEDLINE
Journal :
Clinical and translational science
Publication Type :
Academic Journal
Accession number :
34080309
Full Text :
https://doi.org/10.1111/cts.13082