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Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor

BACKGROUND AND OBJECTIVE: Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib....

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Autores principales: James, Angela Joubert, Smith, Catherine C., Litzow, Mark, Perl, Alexander E., Altman, Jessica K., Shepard, Dale, Kadokura, Takeshi, Souda, Kinya, Patton, Melanie, Lu, Zheng, Liu, Chaofeng, Moy, Selina, Levis, Mark J., Bahceci, Erkut
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550323/
https://www.ncbi.nlm.nih.gov/pubmed/32304015
http://dx.doi.org/10.1007/s40262-020-00888-w
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author James, Angela Joubert
Smith, Catherine C.
Litzow, Mark
Perl, Alexander E.
Altman, Jessica K.
Shepard, Dale
Kadokura, Takeshi
Souda, Kinya
Patton, Melanie
Lu, Zheng
Liu, Chaofeng
Moy, Selina
Levis, Mark J.
Bahceci, Erkut
author_facet James, Angela Joubert
Smith, Catherine C.
Litzow, Mark
Perl, Alexander E.
Altman, Jessica K.
Shepard, Dale
Kadokura, Takeshi
Souda, Kinya
Patton, Melanie
Lu, Zheng
Liu, Chaofeng
Moy, Selina
Levis, Mark J.
Bahceci, Erkut
author_sort James, Angela Joubert
collection PubMed
description BACKGROUND AND OBJECTIVE: Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib. METHODS: The pharmacokinetic profile of gilteritinib was assessed from five clinical studies. RESULTS: Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20–450 mg). Median maximum concentration was reached 2–6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function. CONCLUSIONS: Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment. CLINICAL TRIAL REGISTRATION: NCT02014558, NCT02456883, NCT02571816. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-020-00888-w) contains supplementary material, which is available to authorized users.
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spelling pubmed-75503232020-10-19 Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor James, Angela Joubert Smith, Catherine C. Litzow, Mark Perl, Alexander E. Altman, Jessica K. Shepard, Dale Kadokura, Takeshi Souda, Kinya Patton, Melanie Lu, Zheng Liu, Chaofeng Moy, Selina Levis, Mark J. Bahceci, Erkut Clin Pharmacokinet Original Research Article BACKGROUND AND OBJECTIVE: Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib. METHODS: The pharmacokinetic profile of gilteritinib was assessed from five clinical studies. RESULTS: Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20–450 mg). Median maximum concentration was reached 2–6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function. CONCLUSIONS: Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment. CLINICAL TRIAL REGISTRATION: NCT02014558, NCT02456883, NCT02571816. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-020-00888-w) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-04-18 2020 /pmc/articles/PMC7550323/ /pubmed/32304015 http://dx.doi.org/10.1007/s40262-020-00888-w Text en © The Author(s) 2020 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
James, Angela Joubert
Smith, Catherine C.
Litzow, Mark
Perl, Alexander E.
Altman, Jessica K.
Shepard, Dale
Kadokura, Takeshi
Souda, Kinya
Patton, Melanie
Lu, Zheng
Liu, Chaofeng
Moy, Selina
Levis, Mark J.
Bahceci, Erkut
Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor
title Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor
title_full Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor
title_fullStr Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor
title_full_unstemmed Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor
title_short Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor
title_sort pharmacokinetic profile of gilteritinib: a novel flt-3 tyrosine kinase inhibitor
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550323/
https://www.ncbi.nlm.nih.gov/pubmed/32304015
http://dx.doi.org/10.1007/s40262-020-00888-w
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