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Determining drug dose in the era of targeted therapies: playing it (un)safe?

Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under deve...

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Autores principales: Skånland, Sigrid S., Tjønnfjord, Geir E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9399108/
https://www.ncbi.nlm.nih.gov/pubmed/35999205
http://dx.doi.org/10.1038/s41408-022-00720-7
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author Skånland, Sigrid S.
Tjønnfjord, Geir E.
author_facet Skånland, Sigrid S.
Tjønnfjord, Geir E.
author_sort Skånland, Sigrid S.
collection PubMed
description Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under development. While these therapies act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed in dose-finding studies of various BTK inhibitors, but the minimum doses that result in full BTK occupancy were not determined. Although targeted agents have a different dose–response relationship than cytotoxic agents, which are more effective near the maximum tolerated dose, the traditional 3 + 3 toxicity-driven trial design remains heavily used in the era of targeted therapies. If pharmacodynamic biomarkers were more stringently used to guide dose selection, the recommended phase II dose would likely be lower as compared to the toxicity-driven selection. Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance.
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spelling pubmed-93991082022-08-25 Determining drug dose in the era of targeted therapies: playing it (un)safe? Skånland, Sigrid S. Tjønnfjord, Geir E. Blood Cancer J Review Article Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available and are continuously under development. While these therapies act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed in dose-finding studies of various BTK inhibitors, but the minimum doses that result in full BTK occupancy were not determined. Although targeted agents have a different dose–response relationship than cytotoxic agents, which are more effective near the maximum tolerated dose, the traditional 3 + 3 toxicity-driven trial design remains heavily used in the era of targeted therapies. If pharmacodynamic biomarkers were more stringently used to guide dose selection, the recommended phase II dose would likely be lower as compared to the toxicity-driven selection. Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance. Nature Publishing Group UK 2022-08-23 /pmc/articles/PMC9399108/ /pubmed/35999205 http://dx.doi.org/10.1038/s41408-022-00720-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Review Article
Skånland, Sigrid S.
Tjønnfjord, Geir E.
Determining drug dose in the era of targeted therapies: playing it (un)safe?
title Determining drug dose in the era of targeted therapies: playing it (un)safe?
title_full Determining drug dose in the era of targeted therapies: playing it (un)safe?
title_fullStr Determining drug dose in the era of targeted therapies: playing it (un)safe?
title_full_unstemmed Determining drug dose in the era of targeted therapies: playing it (un)safe?
title_short Determining drug dose in the era of targeted therapies: playing it (un)safe?
title_sort determining drug dose in the era of targeted therapies: playing it (un)safe?
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9399108/
https://www.ncbi.nlm.nih.gov/pubmed/35999205
http://dx.doi.org/10.1038/s41408-022-00720-7
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