Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia
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REVIEW ARTICLE
Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia Juan Eduardo Megías-Vericat 1 & Antonio Solana-Altabella 1 & Octavio Ballesta-López 1 David Martínez-Cuadrón 2,3 & Pau Montesinos 2,3
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Received: 4 May 2020 / Accepted: 13 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Acute myeloid leukemia . Glasdegib . FLT3 inhibitors . Ivosidenib . Enasidenib . Venetoclax
Introduction Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous hematologic cancer characterized by an excess of myeloblasts in bone marrow and blood. Using conventional chemotherapy schedules (3 + 7 or similar), 60–80% of young AML patients achieve complete remission (CR), which might be followed by allogeneic hematopoietic stem cell transplant (allo-HSCT) to prevent relapse [1, 2]. In addition, many AML patients are not considered candidates for
* Pau Montesinos [email protected] 1
Servicio de Farmacia, Área del Medicamento, Hospital Universitari i Politècnic La Fe. Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
2
Servicio de Hematología y Hemoterapia, Hospital Universitari i Politècnic La Fe. Av. Fernando Abril Martorell, 106, 46026 Valencia, Spain
3
CIBERONC, Instituto Carlos III, Madrid, Spain
intensive schemes, and therefore low-intensity regimens are offered to them (i.e., low-dose cytarabine [LDAC] or hypomethylating agents [HMA]) [1, 2]. After decades of treatment using classical cytotoxic agents, physicians are now facing-up a learning process for th
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