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Population Pharmacokinetics of Selumetinib and Its Metabolite N‐desmethyl‐selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low‐Grade Gliomas

Selumetinib (AZD6244, ARRY‐142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N‐...

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Autores principales: Patel, YT, Daryani, VM, Patel, P, Zhou, D, Fangusaro, J, Carlile, DJ, Martin, PD, Aarons, L, Stewart, CF
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445231/
https://www.ncbi.nlm.nih.gov/pubmed/28326681
http://dx.doi.org/10.1002/psp4.12175
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author Patel, YT
Daryani, VM
Patel, P
Zhou, D
Fangusaro, J
Carlile, DJ
Martin, PD
Aarons, L
Stewart, CF
author_facet Patel, YT
Daryani, VM
Patel, P
Zhou, D
Fangusaro, J
Carlile, DJ
Martin, PD
Aarons, L
Stewart, CF
author_sort Patel, YT
collection PubMed
description Selumetinib (AZD6244, ARRY‐142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N‐desmethyl‐selumetinib in patients with cancer. Concentration–time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N‐desmethyl‐selumetinib data were modeled separately. A sequential zero‐ and first‐order absorption with lag time with a two‐compartment model for selumetinib and a two‐compartment model for N‐desmethyl‐selumetinib best described the concentration–time data. Intrapatient variability in absorption was higher than interpatient variability. The apparent drug clearance (CL/F) from the central compartment was 13.5 L/hr (RSE 4.9%). Significant covariates for CL/F were age, alanine aminotransferase, and body surface area. This study confirms that flat dosing is appropriate in adults, whereas body‐surface area based dosing should be used in pediatric patients.
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spelling pubmed-54452312017-05-30 Population Pharmacokinetics of Selumetinib and Its Metabolite N‐desmethyl‐selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low‐Grade Gliomas Patel, YT Daryani, VM Patel, P Zhou, D Fangusaro, J Carlile, DJ Martin, PD Aarons, L Stewart, CF CPT Pharmacometrics Syst Pharmacol Original Articles Selumetinib (AZD6244, ARRY‐142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N‐desmethyl‐selumetinib in patients with cancer. Concentration–time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N‐desmethyl‐selumetinib data were modeled separately. A sequential zero‐ and first‐order absorption with lag time with a two‐compartment model for selumetinib and a two‐compartment model for N‐desmethyl‐selumetinib best described the concentration–time data. Intrapatient variability in absorption was higher than interpatient variability. The apparent drug clearance (CL/F) from the central compartment was 13.5 L/hr (RSE 4.9%). Significant covariates for CL/F were age, alanine aminotransferase, and body surface area. This study confirms that flat dosing is appropriate in adults, whereas body‐surface area based dosing should be used in pediatric patients. John Wiley and Sons Inc. 2017-03-22 2017-05 /pmc/articles/PMC5445231/ /pubmed/28326681 http://dx.doi.org/10.1002/psp4.12175 Text en © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Patel, YT
Daryani, VM
Patel, P
Zhou, D
Fangusaro, J
Carlile, DJ
Martin, PD
Aarons, L
Stewart, CF
Population Pharmacokinetics of Selumetinib and Its Metabolite N‐desmethyl‐selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low‐Grade Gliomas
title Population Pharmacokinetics of Selumetinib and Its Metabolite N‐desmethyl‐selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low‐Grade Gliomas
title_full Population Pharmacokinetics of Selumetinib and Its Metabolite N‐desmethyl‐selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low‐Grade Gliomas
title_fullStr Population Pharmacokinetics of Selumetinib and Its Metabolite N‐desmethyl‐selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low‐Grade Gliomas
title_full_unstemmed Population Pharmacokinetics of Selumetinib and Its Metabolite N‐desmethyl‐selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low‐Grade Gliomas
title_short Population Pharmacokinetics of Selumetinib and Its Metabolite N‐desmethyl‐selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low‐Grade Gliomas
title_sort population pharmacokinetics of selumetinib and its metabolite n‐desmethyl‐selumetinib in adult patients with advanced solid tumors and children with low‐grade gliomas
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445231/
https://www.ncbi.nlm.nih.gov/pubmed/28326681
http://dx.doi.org/10.1002/psp4.12175
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