Clinical uses and safety concerns of tyrosine kinase inhibitors with a focus on novel drugs: A narrative review

Abstract

Objective:To review the safety issues surrounding tyrosine kinase inhibitors (TKIs), specifically, hematological adverse effects, cardiovascular issues, renal adverse effects and nephrotoxicity, endocrine system adverse effects, concerns related to the reproductive system, dermatological and gastrointestinal adverse effects. Data Sources: A literature search was performed through Web of Science, PubMed, Google Scholar, Scopus, and the Food and Drug Administration. Data Summary: Several safety issues have been raised following the use of TKIs. Most TKIs show hematological side effects. Considering cardiovascular toxicities, as opposed to imatinib which is relatively safe, new-generation TKIs may be associated with severe cardiovascular side effects. Both acute and chronic renal failure were reported with TKIs such as gefitinib, imatinib, pazopanib, sorafenib, and sunitinib. Many endocrine adverse effects have been reported including hypercholesterolemia and hypertriglyceridemia (with lorlatinib) and thyroid dysfunction (with dasatinib). TKIs may interfere with fetus implantation, growth, and gonadal development. Females receiving TKIs and encountering unwanted pregnancy may have a normal pregnancy, miscarriage, or an abnormality in the fetus. Skin toxicity has been identified as the most debilitating adverse effect in patients receiving EGFR-TKI. Gastrointestinal side effects are common with TKIs. Diarrhea was the most frequently reported adverse effect of many TKIs. Conclusions: TKIs are increasingly taking up a critical role in the treatment of cancers due to their specific action toward malignant cells compared to conventional cytotoxic chemotherapy. Despite a dramatic improvement in the survival of patients with cancer following approval of TKIs, various early and late adverse effects were reported.

When the unimaginable happens: Lung cancer diagnosis during pregnancy

“…The safety of using TKIs in pregnancy remains an increasingly pressing question because of their potential increased use among young patients with lung cancer. Although some cases report safe TKI use, 16 data are conflicting. In a study of 125 women exposed to imatinib during pregnancy, 63 delivered normal infants and 35 underwent elective terminations; 18 pregnancies ended in spontaneous abortion, and the remaining nine infants were born with congenital abnormalities.…”

Vascular Endothelial Growth Factor C and D Signaling Pathways as Potential Targets for the Treatment of Neovascular Age-Related Macular Degeneration: A Narrative Review

“…Several difficulties with systemic and topical delivery of TKIs in development highlight the challenges associated with those routes of administration for small molecules. When administered systemically, TKIs have been associated with unfavorable side effects, including hematological, cardiovascular, gastrointestinal, and endocrine events; and skin toxicity [ 129 ]. For example, X-82 (an oral pan-VEGFR and PDGFR inhibitor) caused dose-dependent transaminase elevations in several participants of a phase 1 trial in nAMD [ 130 ]; moreover, 29% of patients did not complete the 24-week endpoint, and 17% withdrew as a result of adverse events.…”