Tyrosine kinase inhibitors: A review on pharmacology, metabolism and side effects

Department of Oncology/Hematology/Immunology/Rheumatology/Pneumology, South West German Cancer Center, Eberhard Karls University Tübingen, Germany.
Current Drug Metabolism (Impact Factor: 2.98). 09/2009; 10(5):470-81.
Source: PubMed


Tyrosine kinase inhibitors (TKI) are effective in the targeted treatment of various malignancies. Imatinib was the first to be introduced into clinical oncology, and it was followed by drugs such as gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib. Although they share the same mechanism of action, namely competitive ATP inhibition at the catalytic binding site of tyrosine kinase, they differ from each other in the spectrum of targeted kinases, their pharmacokinetics as well as substance-specific adverse effects. With variations from drug to drug, tyrosine kinase inhibitors cause skin toxicity, including folliculitis, in more than 50% of patients. Among the tyrosine kinase inhibitors that are commercially available as yet, the agents that target EGFR, erlotinib and gefitinib, display the broadest spectrum of adverse effects on skin and hair, including folliculitis, paronychia, facial hair growth, facial erythema, and varying forms of frontal alopecia. In contrast, folliculitis is not common during administration of sorafenib and sunitinib, which target VEGFR, PDGFR, FLT3, and others, whereas both agents have been associated with subungual splinter hemorrhages. Periorbital edema is a common adverse effect of imatinib. Besides the haematological side effects of most of TKIs like anemia, thrombopenia and neutropenia, the most common extra-heamatologic adverse effects are edema, nausea, hypothyroidism, vomiting and diarrhea. Regarding possible long term effects, recently cardiac toxicity with congestive heart failure is under debate in patients receiving imatinib and sunitinib therapy; however, this observation was probably relate to patients selection, although, TKIs overall appear to be a very well tolerated drug class.

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    • "Unwanted side effects affecting the skin organ are mostly non-life-threatening, but can seriously reduce patients’ quality of life and, thus, endanger therapeutic success by reducing compliance.8 From a dermatological point of view, various clinical patterns can be determined; these occur quite frequently and, therefore, have a high practical relevance.9,10 Recommendations for the therapeutical management for some of these patterns exist, the evidence of which is worked on progressively.11,12 "
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    ABSTRACT: Purpose Chemotherapy with anthracyclines, taxanes, or alkylating agents often causes cutaneous side effects. Nonspecific inhibition of the proliferative activity of keratinocytes has antidifferentiation effects that lead to defects in the barrier function and, thus, to dry, itchy, and irritable skin. These cutaneous symptoms reduce the quality of life of the patients considerably. Conditioning with topical application of niacinamide uses the cytoprotective and barrier stabilizing effect of vitamin B3. Patients and methods A multicenter randomized crossover study investigated the influence of the test preparation on the quality of life compared to standard care for 73 patients with breast cancer undergoing adjuvant or neoadjuvant cytostatic therapy. Primary target parameter was the Dermatology Life Quality Index with its respective subscales after 6 weeks of a twice-daily application of the respective preparations. Additionally, specific symptoms such as pruritus, dryness, and irritability have been assessed using visual analog scales. Results Regarding the total score of the Dermatology Life Quality Index, no relevant differences could be observed. However, the results for the “symptoms and feelings” subscale show a significant advantage in favor of the test preparation. Significant superiority of the test preparation could also be observed in the secondary target parameters, the visual analog scales (P<0.05). Conclusion The results show for the first time a significant superiority of prophylactic application of niacinamide for maintaining quality of life while undergoing cytostatic treatment.
    Breast Cancer: Targets and Therapy 08/2014; 6:115-22. DOI:10.2147/BCTT.S61699
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    • "Specific inhibition of oncogenic EGFR alleles may be a promising strategy for therapy for cancer patients carrying causative oncogenic EGFR mutations. Gefitinib and erlotinib are well-known EGFR-tyrosine kinase inhibitors (EGFR-TKIs), and are each currently used as an anticancer drug in the treatment of cancers [6–8]. In addition to such EGFR-TKIs, another agent that has an inhibitory mechanism different from EGFR-TKIs against mutant EGFR, if any, may be useful and necessary for responding to various cancers; and such different agents may compensate for their imperfection to each other in anticancer therapies. "
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    ABSTRACT: Anticancer agents that have minimal effects on normal cells and tissues are ideal cancer drugs. Here, we show specific inhibition of human cancer cells carrying oncogenic mutations in the epidermal growth factor receptor (EGFR) gene by means of oncogenic allele-specific RNA interference (RNAi), both in vivo and in vitro. The allele-specific RNAi (ASP-RNAi) treatment did not affect normal cells or tissues that had no target oncogenic allele, whereas the suppression of a normal EGFR allele by a conventional in vivo RNAi caused adverse effects, i.e., normal EGFR is vital. Taken together, our current findings suggest that specific inhibition of oncogenic EGFR alleles without affecting the normal EGFR allele may provide a safe treatment approach for cancer patients and that ASP-RNAi treatment may be capable of becoming a safe and effective, anticancer treatment method.
    PLoS ONE 08/2013; 8(8):e73214. DOI:10.1371/journal.pone.0073214 · 3.23 Impact Factor
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    • "Axitinib is a member of the tyrosine kinase inhibitors (TKIs), which, as a class, have similarities in absorption, metabolism, and transport characteristics. Many (but not all) have good to complete absorption, with fraction absorbed values greater than 0.3 and some in the 0.6 to 1.0 range (Hartmann et al., 2009). Most are substrates for cytochrome P450s and the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). "
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    ABSTRACT: Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1-3. ABC and SLC transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ≥ 6 x 10(-6) cm/sec). Active efflux was observed in Caco-2 cells and further evaluation in MDR1- or BCRP-transfected MDCK cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not breast cancer resistance protein (BCRP). Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP-transfected MDCK cells with IC50 values of 3 μM and 4.4 μM, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified since an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC50 for each transporter. However, a GastroPlus(TM) simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. OATP1B1 and OATP1B3 transfected HEK293 cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [(14)C]axitinib-equivalents showed rapid absorption and distribution to all tissues except brain. This suggested efflux transport of axitinib may occur at the mouse blood brain barrier.
    Drug metabolism and disposition: the biological fate of chemicals 05/2013; 41(8). DOI:10.1124/dmd.113.051193 · 3.25 Impact Factor
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