Angiogenesis Inhibitors and Hypertension: An Emerging Issue

Abstract

Conception and design: Domenic A. Sica Manuscript writing: Domenic A. Sica Final approval of manuscript: Domenic A. Sica Editorial www.jco.org 1331 from 128.210.126.199 Information downloaded from jco.ascopubs.org and provided by at PURDUE

Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

“…A decrease in tumor perfusion as measured by dynamic contrast enhanced magnetic resonance imaging was observed in patients receiving 800 mg once daily or 300 mg twice daily dose. Hypertension seems to be a class effect of all VEGF signaling inhibitors in the clinic (21) and can be used as a potential pharmacodynamic marker for inhibition of VEGF signaling. There seemed to be a correlation between hypertension and steady-state concentration in phase I study of pazopanib, with 53% of patients achieving C steady-state >46 Amol/L (20 Ag/mL) showing an increase in blood pressure whereas only 18% of patients with C steady-state <46 Amol/L had an increase in blood pressure.…”

Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects

“…[13][14][15][16] Bevacizumab, sorafenib and sunitinib have been shown to increase blood pressure. 1,15,17 The exact pathogenesis by which sunitinib induces hypertension is not yet known.…”

“…It has been speculated that TKIs may exert hypertensive effects directly at the level of the vasculature through processes such as vascular rarefaction, endothelial dysfunction or altered nitrous oxide metabolism. 13,18 Patients receiving sunitinib should be monitored for hypertension and treated, as appropriate, with standard antihypertensive therapy, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, cal- cium-channel blockers (CCBs), β-blockers, and diuretics (e.g., see Canadian Hypertension Guidelines). 19,20 Therapy for hypertension is often required only during the therapy phase and may be discontinued when patients are off the drug.…”

Drug-induced aortic aneurysms, ruptures and dissections

“…The involvement of VEGF in the formation of normal blood vessels during embryonic development and in the carcinogenesis is well studied, but its possible function in normal blood vessels in adults is unclear. Suggested mechanisms include impaired angiogenesis at the microcirculation level, endothelial dysfunction associated with decreased levels of the vasodilator nitric oxide which is normally stimulated by VEGF, and alterations in the reninangiotensin-aldosteron system (Sica, 2006). Based upon the high incidence of hypertension during treatment with VEGF inhibitors, patients treated with these drugs should be closely followed with blood pressure measurements.…”