Lenvatinib, an oral multi-kinases inhibitor, -associated hypertension: Potential role of vascular endothelial dysfunction

• Published in: Atherosclerosis Vol. 260; pp. 116 - 120
• Main Authors: Sueta, Daisuke, Suyama, Koichi, Sueta, Aiko, Tabata, Noriaki, Yamashita, Takayoshi, Tomiguchi, Mai, Takeshita, Takashi, Yamamoto-Ibusuki, Mutsuko, Yamamoto, Eiichiro, Izumiya, Yasuhiro, Kaikita, Koichi, Yamamoto, Yutaka, Hokimoto, Seiji, Iwase, Hirotaka, Tsujita, Kenichi
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.05.2017
• Subjects: Administration, Oral; Aged; Aged, 80 and over; Blood Pressure - drug effects; Blood Pressure - physiology; Blood Pressure Determination; Cardiovascular; Disease Progression; Dose-Response Relationship, Drug; Endothelial dysfunction; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Female; Follow-Up Studies; Humans; Hypertension - chemically induced; Hypertension - epidemiology; Hypertension - physiopathology; Incidence; Japan - epidemiology; Lenvatinib; Male; Middle Aged; Nitric Oxide - blood; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - adverse effects; Prognosis; Prospective Studies; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Quinolines - administration & dosage; Quinolines - adverse effects; Risk Factors; Thyroid Neoplasms - blood; Thyroid Neoplasms - drug therapy; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - blood; Vascular Resistance - drug effects; Endothelial dysfunction; Vascular endothelial growth factor; Lenvatinib
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2017.03.039

Abstract Background and aims Lenvatinib (Lenvima® ), an oral multi-kinase inhibitor, is effective in the treatment of differentiated thyroid carcinomas (DTCs). A severe adverse effect of lenvatinib is hypertension, thus limiting its use as an anti-cancer treatment. Although the pathogenesis of hypertension is generally assumed to involve microvascular bed reduction and an increase in peripheral vascular resistance due to a decrease in nitrogen oxide (NOx) production after vascular endothelial growth factor (VEGF) inhibition, the effects of hypertension on vascular endothelial function in actual patients remain unclear. Here, we examined how lenvatinib affects vascular endothelial function. Methods Ten consecutive DTC patients who did not take any cardiovascular agents were orally administered 24 mg of lenvatinib once daily. Using an EndoPAT2000® system, we used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of the RH-PAT index (RHI). We expressed the results as %RHI, which indicates the change compared with pretreatment levels. Additionally, we measured serum NOx and plasma VEGF concentrations pre- and post-treatment. Results All of the patients treated with lenvatinib exhibited significant hypertension; the %RHI levels were significantly decreased the day after treatment with lenvatinib. Furthermore, serum NOx and plasma VEGF concentrations were significantly decreased and increased, respectively, compared with pretreatment levels. These results indicate that hypertension induced by lenvatinib may be caused by a decrease in nitric oxide production, as a result of VEGF inhibition and impaired vascular endothelial function. Conclusions We provide the first demonstration that lenvatinib causes hypertension via vascular endothelial dysfunction in human subjects.