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And Nilotinib Drug Interactions with the Tyrosine Kinase Inhibitors Imatinib From bloodjournal.hematologylibrary.org by guest on May 10, 2013. For personal use only. 2011 117: e75-e87 Prepublished online September 1, 2010; doi:10.1182/blood-2010-07-294330 Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib Amina Haouala, Nicolas Widmer, Michel A. Duchosal, Michael Montemurro, Thierry Buclin and Laurent A. Decosterd Updated information and services can be found at: http://bloodjournal.hematologylibrary.org/content/117/8/e75.full.html Articles on similar topics can be found in the following Blood collections Clinical Trials and Observations (3705 articles) e-Blood (104 articles) Myeloid Neoplasia (943 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. From bloodjournal.hematologylibrary.org by guest on May 10, 2013. For personal use only. MYELOID NEOPLASIA e-Blood Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib Amina Haouala,1 Nicolas Widmer,1 Michel A. Duchosal,2 Michael Montemurro,3 Thierry Buclin,1 and Laurent A. Decosterd1 1Division of Clinical Pharmacology and Toxicology, 2Service and Central Laboratory of Hematology, and 3Multidisciplinary Oncology Centre, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland Several cancer treatments are shifting dasatinib. TKIs are prescribed for pro- prescribed co-medications, including from traditional, time-limited, nonspecific longed periods, often in patients with known inhibitors or inducers of cyto- cytotoxic chemotherapy cycles to continu- comorbidities. Therefore, they are regu- chromes P450 or drug transporters. Infor- ous oral treatment with specific protein- larly co-administered along with treat- mation is mostly available for imatinib targeted therapies. In this line, imatinib ments at risk of drug-drug interactions. mesylate, well introduced in clinical prac- mesylate, a selective tyrosine kinases This aspect has been partially addressed tice. Several pharmacokinetic aspects yet inhibitor (TKI), has excellent efficacy in so far, calling for a comprehensive review remain insufficiently investigated for the treatment of chronic myeloid leuke- of the published data. We review here the these drugs. Regular updates will be man- mia. It has opened the way to the develop- available evidence and pharmacologic datory and so is the prospective report- ment of additional TKIs against chronic mechanisms of interactions between ima- ing of unexpected clinical observations. myeloid leukemia, including nilotinib and tinib, dasatinib, and nilotinib and widely (Blood. 2011;117(8):e75-e87) Introduction Targeted cancer therapies have been designed to interact with concentration profiles from one patient to another, thus favoring the particular proteins associated with tumor development or progres- selection of resistant cellular clones by subtherapeutic drug expo- sion. Many of these agents are tyrosine kinases inhibitors (TKIs), sure or the occurrence of toxicity in case of overexposure.14,15 targeting enzymes whose disregulated expression and activity are Identifying the best active and safe dosing schedule for individual associated with various cancers.1 The pioneer small-molecule TKI patients to maximize therapeutic benefit has become a scientific imatinib has revolutionized the treatment and prognosis of chronic and clinical challenge. Combination therapies have been investi- myeloid leukemia (CML). Imatinib inhibits the tyrosine kinase gated in various conditions, which certainly add a level of Bcr-Abl,2 a fusion oncoprotein resulting from the translocation treatment complexity, because overlapping toxicities and pharma- t(9;22)(q34;q11),3 which is associated with the characteristic cokinetic interactions have to be taken into consideration.16,17 Philadelphia chromosome,2 a hallmark of chronic myeloid leuke- We review here systematically and present under an easy- mia and of some acute lymphoblastic leukemias.4 consulting form (Table 1) the information available on pharmaco- However, some patients, especially those in the advanced phase logic interactions between imatinib, dasatinib, and nilotinib and of the disease, develop resistance to imatinib therapy, because of drugs concomitantly prescribed to patients receiving TKIs. The various mechanisms such as BCR-ABL gene amplification,5 low drugs were selected on the basis of the information extracted from imatinib absorption, or more frequently point mutations into the our database, used within the framework of Therapeutic Drug 15 oncoprotein sequence.6 Several new inhibitors have been devel- Monitoring of TKIs. Moreover, classical inhibitors or inducers of oped with increased potency and a broader range of activity against cytochromes P450 or drug transporters were also included in this imatinib-resistant mutants. In vitro studies have shown that nilo- review. We do not intend here to replace individualized medical evaluation, and the data presented here should be used in addition tinib, an imatinib derivative, and dasatinib, structurally unrelated to to thorough clinical judgment. Indeed, it may be that our searches imatinib, are, respectively, 20- and 300-fold more potent than still missed some interactions, and actually most interactions do not imatinib against unmutated Abl7 and are active against many represent true contraindications but rather call for appropriate imatinib-resistant Bcr-Abl mutants.7 dosage adjustments and treatment monitoring measures. TKIs are extensively metabolized by cytochrome P450 en- zymes (CYP), whose activities are characterized by a large degree of interindividual variability.8 Some TKIs are also substrates or Review of the literature inhibitors of the drug transporters P-glycoprotein (Pgp; coded by ABCB1) Breast Cancer Resistance Protein (BCRP; ABCG2) and In addition to official monographs of the drugs,9 literature from Medline the organic cation transporter 1 (hOCT1; SLC22A1).9-13 A standard and Evidence-Based Medicine Reviews was systematically searched, regimen can therefore produce very different circulating and cell using the following MeSH terms: “Drug interactions,” “Cytochrome Submitted July 5, 2010; accepted August 21, 2010. Prepublished online as payment. Therefore, and solely to indicate this fact, this article is hereby Blood First Edition paper, September 1, 2010; DOI 10.1182/blood-2010-07- marked ‘‘advertisement’’ in accordance with 18 USC section 1734. 294330. The publication costs of this article were defrayed in part by page charge © 2011 by The American Society of Hematology BLOOD, 24 FEBRUARY 2011 ⅐ VOLUME 117, NUMBER 8 e75 From bloodjournal.hematologylibrary.org by guest on May 10, 2013. For personal use only. e76 HAOUALA et al BLOOD, 24 FEBRUARY 2011 ⅐ VOLUME 117, NUMBER 8 Table 1 (in 10 parts) summarizes observed or potential drug interactions between TKIs and commonly concomitantly prescribed drugs or classical interacting agents (lines) sorted according to the ATC classification. The arrows 1 and 2 indicate an increase or decrease of drug concentration, respectively. Boldface text outlines interactions reported in the literature (reference number), whereas standard characters represent potential interactions predicted from theoretical considerations (but not yet reported in the literature). “Absence of interaction” means that a clinical study concluded to the absence of interaction (reference number), and “—” means that no interaction is either reported or theoretically expected. Part 1. Alimentary tract and metabolism Imatinib Dasatinib Nilotinib PPI Omeprazole ● Inhibition of Pgp by omeprazole: ● 2 dasatinib absorption9 — 1 imatinib exposure9,18,64 (2 dasatinib solubility) ● Inhibition of Pgp by omeprazole: 1 dasatinib exposure9,18,64 Esomeprazole ● Inhibition of Pgp by esomeprazole: ● 2 dasatinib absorption9 — 1 imatinib exposure9,18,64 (2 dasatinib solubility) ● Inhibition of Pgp by esomeprazole: 1 dasatinib exposure9,18,64 Pantoprazole ● Inhibition of Pgp by pantoprazole: ● 2 dasatinib absorption9 — 1 imatinib exposure9,18,64 (2 dasatinib solubility) ● Inhibition of Pgp by pantoprazole: 1 dasatinib exposure9,18,64 H2-antagonists Cimetidine ● Inhibition of CYP 3A4 and Pgp by cimetidine: ● 2 dasatinib absorption9 ● Inhibition of CYP 3A4 by cimetidine: 1 imatinib exposure18,65 (2 dasatinib solubility) 1 nilotinib exposure18,65 ● Inhibition of hOCT1 by cimetidine: ● Inhibition of CYP 3A4 and Pgp by cimetidine: 2 imatinib intracellular exposure18,64,65 1 dasatinib exposure18,65 Ranitidine ● Inhibition of Pgp by ranitidine: ● 2 dasatinib absorption9 — 1 imatinib exposure18,65 (2 dasatinib solubility) ● Inhibition of hOCT1 by ranitidine: ● Inhibition of Pgp by ranitidine: 2 imatinib intracellular exposure9,18,64,65 1 dasatinib exposure18,65 Antiemetics Metoclopramide — ● 1 QT interval19 (additive effect) ● 1 QT interval19 (additive effect) 3 monitor ECG 3 monitor ECG Antidiabetic drugs Insulin — — — Metformin
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