Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

Targeted cancer therapies have been designed to interact with particular proteins associated with tumor development or progression. Many of these agents are tyrosine kinases inhibitors (TKIs), targeting enzymes whose disregulated expression and activity are associated with various cancers.¹  The pioneer small-molecule TKI imatinib has revolutionized the treatment and prognosis of chronic myeloid leukemia (CML). Imatinib inhibits the tyrosine kinase Bcr-Abl,²  a fusion oncoprotein resulting from the translocation t(9;22)(q34;q11),³  which is associated with the characteristic Philadelphia chromosome,²  a hallmark of chronic myeloid leukemia and of some acute lymphoblastic leukemias.⁴ 

However, some patients, especially those in the advanced phase of the disease, develop resistance to imatinib therapy, because of various mechanisms such as BCR-ABL gene amplification,⁵  low imatinib absorption, or more frequently point mutations into the oncoprotein sequence.⁶  Several new inhibitors have been developed with increased potency and a broader range of activity against imatinib-resistant mutants. In vitro studies have shown that nilotinib, an imatinib derivative, and dasatinib, structurally unrelated to imatinib, are, respectively, 20- and 300-fold more potent than imatinib against unmutated Abl⁷  and are active against many imatinib-resistant Bcr-Abl mutants.⁷ 

TKIs are extensively metabolized by cytochrome P450 enzymes (CYP), whose activities are characterized by a large degree of interindividual variability.⁸  Some TKIs are also substrates or inhibitors of the drug transporters P-glycoprotein (Pgp; coded by ABCB1) Breast Cancer Resistance Protein (BCRP; ABCG2) and the organic cation transporter 1 (hOCT1; SLC22A1).^9–13  A standard regimen can therefore produce very different circulating and cell concentration profiles from one patient to another, thus favoring the selection of resistant cellular clones by subtherapeutic drug exposure or the occurrence of toxicity in case of overexposure.^14,15  Identifying the best active and safe dosing schedule for individual patients to maximize therapeutic benefit has become a scientific and clinical challenge. Combination therapies have been investigated in various conditions, which certainly add a level of treatment complexity, because overlapping toxicities and pharmacokinetic interactions have to be taken into consideration.^16,17 

We review here systematically and present under an easy-consulting form (Table 1) the information available on pharmacologic interactions between imatinib, dasatinib, and nilotinib and drugs concomitantly prescribed to patients receiving TKIs. The drugs were selected on the basis of the information extracted from our database, used within the framework of Therapeutic Drug Monitoring of TKIs.¹⁵  Moreover, classical inhibitors or inducers of cytochromes P450 or drug transporters were also included in this review. We do not intend here to replace individualized medical evaluation, and the data presented here should be used in addition to thorough clinical judgment. Indeed, it may be that our searches still missed some interactions, and actually most interactions do not represent true contraindications but rather call for appropriate dosage adjustments and treatment monitoring measures.

In addition to official monographs of the drugs,⁹  literature from Medline and Evidence-Based Medicine Reviews was systematically searched, using the following MeSH terms: “Drug interactions,” “Cytochrome P-450 Enzyme System,” “P-Glycoprotein,” “ABCG2 protein,” “organic cation transporter 1,” “Protein binding,” and the respective TKI and concomitant drugs names. In addition, 2 drug information databases (UpToDate online¹⁸  and Cancer Care Ontario¹⁹ ) were screened, and abstracts of international and national conferences, review articles, and references given in identified articles were also scanned.^20–22  All relevant cited literature on pharmacokinetic or pharmacodynamic interactions was considered for inclusion in Table 1.