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Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia

  • Review Article
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Abstract

Several small molecule inhibitors (SMIs) have been recently approved for AML patients. These targeted therapies could be more tolerable than classical antineoplastics, but potential drug-drug interactions (DDI) are relatively frequent. Underestimation or lack of appropriate awareness and management of DDIs with SMIs can jeopardize therapeutic success in AML patients, which often require multiple concomitant medications in the context of prior comorbidities or for the prevention and treatment of infectious and other complications. In this systematic review, we analyze DDIs of glasdegib, venetoclax, midostaurin, quizartinib, gilteritinib, enasidenib, and ivosidenib. CYP3A4 is the main enzyme responsible for SMIs metabolism, and strong CYP3A4 inhibitors, such azoles, could increase drug exposure and toxicity; therefore dose adjustments (venetoclax, quizartinib, and ivosidenib) or alternative therapies or close monitoring (glasdegib, midostaurin, and gilteritinib) are recommended. Besides, coadministration of strong CYP3A4 inducers with SMIs should be avoided due to potential decrease of efficacy. Regarding tolerability, QTc prolongation is frequently observed for most of approved SMIs, and drugs with a potential to prolong the QTc interval and CYP3A4 inhibitors should be avoided and replaced by alternative treatments. In this study, we critically assess the DDIs of SMIs, and we summarize best management options for these new drugs and concomitant medications.

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Funding

This study was supported in part by a grant from the “Instituto Carlos III” (PI16/00665) and the “Instituto Investigacion Sanitaria La Fe” (2019/052-1) assigned to the Pharmacy and Hematology Departments.

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Authors and Affiliations

  1. Servicio de Farmacia, Área del Medicamento, Hospital Universitari i Politècnic La Fe. Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain

    Juan Eduardo Megías-Vericat, Antonio Solana-Altabella & Octavio Ballesta-López

  2. Servicio de Hematología y Hemoterapia, Hospital Universitari i Politècnic La Fe. Av. Fernando Abril Martorell, 106, 46026, Valencia, Spain

    David Martínez-Cuadrón & Pau Montesinos

  3. CIBERONC, Instituto Carlos III, Madrid, Spain

    David Martínez-Cuadrón & Pau Montesinos

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  1. Juan Eduardo Megías-Vericat
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Correspondence to Pau Montesinos.

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Conflict of interest

Pau Montesinos reports these potential conflicts of interest, AbbVie: advisory board, speakers bureau, research support; Astellas: research support, consultant, speakers bureau, advisory board; Agios: consultant; Tolero Pharmaceutical: consultant; Glycomimetics: consultant; Forma Therapeutics: consultant; Celgene: research support, consultant, speakers bureau, advisory board; Daiichi Sankyo: research support, consultant, speakers bureau, advisory board; Incyte: speakers bureau, advisory board; Janssen: research support, speakers bureau, advisory board; Karyopharm: research support, advisory board; Novartis: research support, speakers bureau, advisory board; Pfizer: research support, speakers bureau, advisory board; Teva: research support, speakers bureau, advisory board. The rest of authors declare that there are no competing financial interests in relation to the work described.

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Megías-Vericat, J.E., Solana-Altabella, A., Ballesta-López, O. et al. Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia. Ann Hematol 99, 1989–2007 (2020). https://doi.org/10.1007/s00277-020-04186-0

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  • DOI: https://doi.org/10.1007/s00277-020-04186-0

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