Tyrosine Kinase Inhibitors – A Review on Pharmacology, Metabolism and Side Effects

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.

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

“…Also the subsequent rapid decline and the final slower decline with an elimination half-life of 34.5 h is in line with previous studies [9]. Lenvatinib's rapid absorption, long terminal elimination half-life and large apparent volume of distribution (V z /F=336 L), are similar to those of other tyrosine kinase inhibitors [3,16]. The lower percentage of lenvatinib and total radioactivity in whole blood as compared to plasma (29 % and 36 % lower, respectively) suggest that lenvatinib and lenvatinib-related products are less well distributed into red blood cells.…”

“…Adverse events observed in this study that were considered probably treatment-related were mainly of gastrointestinal origin and were comparable with side effects observed for other tyrosine kinase inhibitors [3]. Although designed as a secondary objective, antitumor activity of lenvatinib may have been observed, since partial response was observed in one and stable disease in three of the total six patients, as the best overall tumor response.…”

“…Over the last decade, several anticancer drugs, targeting various spectra of receptor tyrosine kinases, have been developed and approved. Multitargeted tyrosine kinase inhibitors have shown notable clinical results [3].…”

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

“…In addition, sorafenib-induced multikinase inhibition causes various cutaneous adverse reactions through its off-target effects (31). In the mouse model, we also found elevation of alanine aminotransferase levels in the sorafenib group, compared with the SC-1 and control groups (209 vs. 143 vs. 120 U/L, n = 2 in each group).…”

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

“…Furthermore, a large interindividual pharmacokinetic variability of sorafenib has contributed to the toxicity caused by systemic overexposure [13][14][15]. At present, hypertension, hypothyroidism, hand-foot syndrome and fatigue are attributed to the inhibitory effect on several tyrosine kinases, whereas hypertension, arterial thromboembolic events (ATEs), proteinuria, wound complications, haemorrhage and gastrointestinal perforation have a closer relationship with the inhibition of the VEGF pathway [16][17][18]. Although most adverse events are well tolerated and manageable, the unexpected toxicity profiles (e.g.…”