Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan

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....

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Autores principales:	Ying Hong, Tomoko Ishizuka, Akiko Watanabe, Masaya Tachibana, Mark Lee, Hitoshi Ishizuka, Frank LaCreta, Malaz Abutarif
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/e9cdb914f78a466084a85f5aa18226a3
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spelling	oai:doaj.org-article:e9cdb914f78a466084a85f5aa18226a32021-11-19T17:51:34ZModel‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan1752-80621752-805410.1111/cts.13082https://doaj.org/article/e9cdb914f78a466084a85f5aa18226a32021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13082https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract 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 (AUCinf) 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.Ying HongTomoko IshizukaAkiko WatanabeMasaya TachibanaMark LeeHitoshi IshizukaFrank LaCretaMalaz AbutarifWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2220-2230 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Ying Hong Tomoko Ishizuka Akiko Watanabe Masaya Tachibana Mark Lee Hitoshi Ishizuka Frank LaCreta Malaz Abutarif Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan
description	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 (AUCinf) 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.
format	article
author	Ying Hong Tomoko Ishizuka Akiko Watanabe Masaya Tachibana Mark Lee Hitoshi Ishizuka Frank LaCreta Malaz Abutarif
author_facet	Ying Hong Tomoko Ishizuka Akiko Watanabe Masaya Tachibana Mark Lee Hitoshi Ishizuka Frank LaCreta Malaz Abutarif
author_sort	Ying Hong
title	Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan
title_short	Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan
title_full	Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan
title_fullStr	Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan
title_full_unstemmed	Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan
title_sort	model‐based assessments of cyp3a‐mediated drug‐drug interaction risk of milademetan
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/e9cdb914f78a466084a85f5aa18226a3
work_keys_str_mv	AT yinghong modelbasedassessmentsofcyp3amediateddrugdruginteractionriskofmilademetan AT tomokoishizuka modelbasedassessmentsofcyp3amediateddrugdruginteractionriskofmilademetan AT akikowatanabe modelbasedassessmentsofcyp3amediateddrugdruginteractionriskofmilademetan AT masayatachibana modelbasedassessmentsofcyp3amediateddrugdruginteractionriskofmilademetan AT marklee modelbasedassessmentsofcyp3amediateddrugdruginteractionriskofmilademetan AT hitoshiishizuka modelbasedassessmentsofcyp3amediateddrugdruginteractionriskofmilademetan AT franklacreta modelbasedassessmentsofcyp3amediateddrugdruginteractionriskofmilademetan AT malazabutarif modelbasedassessmentsofcyp3amediateddrugdruginteractionriskofmilademetan
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Model‐based assessments of CYP3A‐mediated drug‐drug interaction risk of milademetan

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