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

ABSTRACT 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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    • "Therefore, RTKs are important therapeutic targets in anti-cancer drug design. Sunitinib, N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2- oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3- carboxamide, marketed as Sutent ® by Pfizer, is an oral, small-molecule, multi-targeted RTK inhibitor approved by the US Food and Drug Administration in 2006 for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumour (Cabebe and Wakelee, 2006; Hartmann et al., 2009). Despite the impressive effectiveness of sunitinib treatment, several cases of liver failure and fatality were documented in clinical trials and post-marketing surveys. "
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    ABSTRACT: Background and purpose: Famitinib is a novel multi-targeted receptor tyrosine kinase inhibitor under development for cancer treatment. This study aims to characterize the metabolic and bioactivation pathways of famitinib. Experimental approach: The metabolites in human plasma, urine and feces were identified via ultra-high performance liquid chromatography-quadrupole-time of flight-mass spectrometry and confirmed using synthetic standards. Biotransformation and bioactivation mechanisms were investigated using microsomes, recombinant metabolic enzymes and hepatocytes. Key results: Famitinib was extensively metabolized after repeated oral administrations. Unchanged famitinib was the major circulating material, followed by N-desethylfaminitib (M3), whose steady-state exposure represented 7.2 to 7.5% that of the parent drug. Metabolites in the excreta were mainly from oxidative deamination (M1), N-desethylation (M3), oxidative defluorination (M7), indolylidene hydroxylation (M9-1 and M9-5) and secondary phase-II conjugations. CYP3A4/5 was the major contributor to M3 formation, CYP3A4/5 and aldehyde dehydrogenase to M1 formation and CYP1A1/2 to M7, M9-1 and M9-5 formations. Minor cysteine conjugates were observed in the plasma, urine and feces, implying the formation of reactive intermediate(s). In vitro microsomal studies proved that famitinib was bioactivated through epoxidation at indolylidene by CYP1A1/2 and spontaneously defluorinated rearrangement to afford a quinone-imine species. A correlation between famitinib hepatotoxicity and its bioactivation was observed in the primary human hepatocytes. Conclusion and implications: Famitinib is well absorbed and extensively metabolized in cancer patients. Multiple enzymes, mainly CYP3A4/5 and CYP1A1/2, are involved in famitinib metabolic clearance. The quinone-imine intermediate formed through bioactivation may be associated with famitinib hepatotoxicity. Co-administered CYP1A1/2 inducers or inhibitors may potentiate or suppress its hepatotoxicity.
    British Journal of Pharmacology 11/2012; 168(7). DOI:10.1111/bph.12047 · 4.84 Impact Factor
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